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Physiological Systems in Promoting Frailty

Laís R. Perazza, Holly M. Brown‐Borg, LaDora V. Thompson

10.1002/cphy.c210034

Source: Volume 12, Issue 3, July 2022

Published online: April 2022

Full Article on Wiley Online Library



Abstract

Frailty is a complex syndrome affecting a growing sector of the global population as medical developments have advanced human mortality rates across the world. Our current understanding of frailty is derived from studies conducted in the laboratory as well as the clinic, which have generated largely phenotypic information. Far fewer studies have uncovered biological underpinnings driving the onset and progression of frailty, but the stage is set to advance the field with preclinical and clinical assessment tools, multiomics approaches together with physiological and biochemical methodologies. In this article, we provide comprehensive coverage of topics regarding frailty assessment, preclinical models, interventions, and challenges as well as clinical frameworks and prevalence. We also identify central biological mechanisms that may be at play including mitochondrial dysfunction, epigenetic alterations, and oxidative stress that in turn, affect metabolism, stress responses, and endocrine and neuromuscular systems. We review the role of metabolic syndrome, insulin resistance and visceral obesity, focusing on glucose homeostasis, adenosine monophosphate‐activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and nicotinamide adenine dinucleotide (NAD+) as critical players influencing the age‐related loss of health. We further focus on how immunometabolic dysfunction associates with oxidative stress in promoting sarcopenia, a key contributor to slowness, weakness, and fatigue. We explore the biological mechanisms involved in stem cell exhaustion that affect regeneration and may contribute to the frailty‐associated decline in resilience and adaptation to stress. Together, an overview of the interplay of aging biology with genetic, lifestyle, and environmental factors that contribute to frailty, as well as potential therapeutic targets to lower risk and slow the progression of ongoing disease is covered. © 2022 American Physiological Society. Compr Physiol 12:3575‐3620, 2022.

Figure 1. Figure 1. Health, frailty, and aging. Frailty is characterized by a loss of health and is classified as an age‐related medical syndrome that features the progressive reduction of health‐promoting capacities. The health‐promoting capacities are determined by functional capacities, when referring to both resilience and resistance abilities, and intrinsic capacities, when referring to physiological reserves. The substantial loss of these capacities increases the risk of frailty via dysregulation of multiple physiological systems. At the molecular level, epigenetic alterations, genomic instability, mitochondrial dysfunction, and oxidative stress are great contributors to impaired physiology that includes metabolic, energy homeostasis and endocrine dysfunction, chronic inflammation as well as impaired hypothalamic‐pituitary‐adrenal (HPA) axis response. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
Figure 2. Figure 2. Conceptualization of physical frailty during the first decade of the 21st century 599. Because the clinical signs and symptoms were known to be physiologically related to one another, in theory, they provided possible connections between molecular alterations associated with aging, physiological decline, and clinical systems. These biological connections were organized conceptually. In aging, the combination of gene variation, DNA damage, and telomere shortening contribute to oxidative stress, mitochondrial dysfunction, cell senescence, and inflammation that in turn, promotes a decline in the physiological functioning of the organism. The aging‐related physiological decline occurs following chronic unresolved inflammation along with neuroendocrine dysregulation triggering anorexia, sarcopenia, and osteopenia, which are conditions related to body, muscle, and bone mass loss. This systemic loss and tissue dysfunction as well as the associated cognitive decline lead to the clinical signs of frailty: slowness, weakness, weight loss, low activity, and fatigue. This conceptualization emphasized the complexity of the multiple systems and visually suggested the manifestations of frailty were a cumulative outcome of dysregulation of these multiple systems. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
Figure 3. Figure 3. Biology of frailty. The two well‐established conceptual frameworks defining the biology of aging are the Seven Pillars of Aging proposed by Kennedy et al. in 300 and the Hallmarks of Aging proposed by López‐Otin et al. in 359 The Seven Pillars define the biological areas that likely contribute to the pathophysiology of aging and include metabolism, epigenetics, inflammation, macro‐molecular damage, adaptation to stress, loss of proteostasis, and stem cells and regeneration. Similarly, the Hallmarks of Aging categorize the cellular and molecular processes that may lead to the aging phenotype as (i) the primary hallmarks—genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis; (ii) the antagonistic hallmarks—dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence; and (iii) the integrative hallmarks—stem cell exhaustion and altered intercellular communication. Together, these two concepts identify potential routes to be targeted to extend healthspan and prevent or reduce frailty. The pillar of metabolism defines the signal transition pathways linked to the metabolism of aging, such as impaired glucose homeostasis and dysregulated nutrient sensing, whereas the epigenetics pillar links age‐related environmental pressures altering the gene function, which might trigger genomic instability. The macro‐molecular damage pillar is also illustrated as a primary hallmark as genomic instability and telomere attrition, which are all considered the causes of damage that might evolve to antagonistic hallmarks that are the response to damage and includes mitochondrial dysfunction and cellular senescence. The adaptation to stress illustrates the loss of resilience and resistance or how well the organism can combat and recover from a stressor, which might be molecular (loss of proteostasis, genomic instability), cellular (macromolecular damage accumulated in stem cells, stem cell function decline) or physiological (altered intercellular communication). Once the organism reaches the integrative hallmark level, a systemic dysfunction is reached, culminating in the Frailty Phenotype. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
Figure 4. Figure 4. The current clinically Based conceptualization of frailty 160,450,597. Integrating the clinical manifestations of frailty with the hallmarks/pillars of aging results in the current conceptualization. Mitochondrial dysfunction, epigenetic alterations, and oxidative stress represent cellular/molecular factors that contribute to three central physiological systems that promote the Frailty Phenotype. The mitochondrial dysfunction accounts for a reduction in the efficiency of oxidative phosphorylation and a reduction in the energy production generating long‐term exhaustion/fatigue. Epigenetic alterations such as DNA methylation and histone modifications are triggered by chronological aging and environmental factors, influencing pathways of health and longevity. Lastly, oxidative stress refers to excessive production of reactive oxygen species (ROS) that leads to cell and tissue damage. The metabolic system represents pathways that are centrally mediated by nutrient‐sensing mechanisms, in which the glucose metabolism, insulin signaling cascade as well as AMP‐activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+) are pivotal players. The stress‐response system is mainly influenced by the hypothalamic‐pituitary‐adrenal (HPA) axis, the autonomic nervous system, and by the immune system. The cognitive and muscular declines, here illustrated by the neuromuscular category, are driven by tissue waste and dysfunction, leading to weight loss, weakness, fatigue, low activity, and slow gait at the organismal level. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
Figure 5. Figure 5. Inflammaging. The biology underlying inflammaging is multifactorial. The mechanisms that contribute to inappropriate inflammatory responses and ultimately low‐level chronic inflammaging include cellular senescence, mitochondrial dysfunction, oxidative stress, visceral adiposity, gut dysbiosis, genetic predisposition, and epigenetics factors such as microRNAs. Potential mediators contributing to the chronic inflammation have both local and systemic impacts that likely promote physical decline. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
Figure 6. Figure 6. Caloric restriction. Caloric restriction is the most well‐established longevity‐modulating intervention. Importantly, dietary restriction whether caloric (protein, carbohydrates, fat), intermittent feeding, or fasting improves health by decreasing morbidities that are associated with aging including frailty. It does so through alterations in energy restriction pathways. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
Figure 7. Figure 7. Sarcopenia. Sarcopenia is the natural event that is characterized by muscle loss and function. At the muscle fiber level, it is observed as a reduction in the fiber quality, size, and number. There is also a reduction in the number and quality of satellite cells, which are stem cells that promote skeletal muscle homeostasis and repair. In the muscle cell, the sarcopenic process is not only driven by increased protein degradation and decreased synthesis, but also by oxidative stress, insulin resistance, ectopic fat accumulation, and inflammation. Multiple signaling pathways provide avenues for therapeutic intervention. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
Figure 8. Figure 8. Physiological systems promoting frailty. Frailty involves a multiple organ network that deteriorates with age and features a decline in functional reserves of many physiological systems. There are common impaired responses observed in many organs of the individual with frailty including inflammation, oxidative stress, ectopic fat accumulation, and insulin resistance. The liver is a central player in metabolism and has thus a key role in the aging process. In frailty, there is an increase in de novo lipogenesis that refers to the biochemical synthesis of fatty acids from the carbohydrate catabolism, boosting ectopic fat accumulation. The fatty liver, combined with inflammation and oxidative stress, promotes hepatocyte injury, facilitating fibrosis (collagen production), stem cell activation, and even cancer development. Muscle is also central to the biology of frailty and is the main organ system contributing to the Frailty Phenotype as muscle mass loss and protein degradation trigger weakness, slowness, and weight loss. As compared to subcutaneous adiposity, visceral adiposity is the most detrimental to health due to its pro‐inflammatory profile. The increased inflammation, ectopic fat accumulation, and oxidative stress are all risk factors to cardiovascular events by facilitating endothelial dysfunction, aortic stiffness, and clotting. On top of that, increased visceral adiposity and hepatic de novo lipogenesis promote dyslipidemia, which also contributes to cardiovascular dysfunction. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 1. Health, frailty, and aging. Frailty is characterized by a loss of health and is classified as an age‐related medical syndrome that features the progressive reduction of health‐promoting capacities. The health‐promoting capacities are determined by functional capacities, when referring to both resilience and resistance abilities, and intrinsic capacities, when referring to physiological reserves. The substantial loss of these capacities increases the risk of frailty via dysregulation of multiple physiological systems. At the molecular level, epigenetic alterations, genomic instability, mitochondrial dysfunction, and oxidative stress are great contributors to impaired physiology that includes metabolic, energy homeostasis and endocrine dysfunction, chronic inflammation as well as impaired hypothalamic‐pituitary‐adrenal (HPA) axis response. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 2. Conceptualization of physical frailty during the first decade of the 21st century 599. Because the clinical signs and symptoms were known to be physiologically related to one another, in theory, they provided possible connections between molecular alterations associated with aging, physiological decline, and clinical systems. These biological connections were organized conceptually. In aging, the combination of gene variation, DNA damage, and telomere shortening contribute to oxidative stress, mitochondrial dysfunction, cell senescence, and inflammation that in turn, promotes a decline in the physiological functioning of the organism. The aging‐related physiological decline occurs following chronic unresolved inflammation along with neuroendocrine dysregulation triggering anorexia, sarcopenia, and osteopenia, which are conditions related to body, muscle, and bone mass loss. This systemic loss and tissue dysfunction as well as the associated cognitive decline lead to the clinical signs of frailty: slowness, weakness, weight loss, low activity, and fatigue. This conceptualization emphasized the complexity of the multiple systems and visually suggested the manifestations of frailty were a cumulative outcome of dysregulation of these multiple systems. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 3. Biology of frailty. The two well‐established conceptual frameworks defining the biology of aging are the Seven Pillars of Aging proposed by Kennedy et al. in 300 and the Hallmarks of Aging proposed by López‐Otin et al. in 359 The Seven Pillars define the biological areas that likely contribute to the pathophysiology of aging and include metabolism, epigenetics, inflammation, macro‐molecular damage, adaptation to stress, loss of proteostasis, and stem cells and regeneration. Similarly, the Hallmarks of Aging categorize the cellular and molecular processes that may lead to the aging phenotype as (i) the primary hallmarks—genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis; (ii) the antagonistic hallmarks—dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence; and (iii) the integrative hallmarks—stem cell exhaustion and altered intercellular communication. Together, these two concepts identify potential routes to be targeted to extend healthspan and prevent or reduce frailty. The pillar of metabolism defines the signal transition pathways linked to the metabolism of aging, such as impaired glucose homeostasis and dysregulated nutrient sensing, whereas the epigenetics pillar links age‐related environmental pressures altering the gene function, which might trigger genomic instability. The macro‐molecular damage pillar is also illustrated as a primary hallmark as genomic instability and telomere attrition, which are all considered the causes of damage that might evolve to antagonistic hallmarks that are the response to damage and includes mitochondrial dysfunction and cellular senescence. The adaptation to stress illustrates the loss of resilience and resistance or how well the organism can combat and recover from a stressor, which might be molecular (loss of proteostasis, genomic instability), cellular (macromolecular damage accumulated in stem cells, stem cell function decline) or physiological (altered intercellular communication). Once the organism reaches the integrative hallmark level, a systemic dysfunction is reached, culminating in the Frailty Phenotype. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 4. The current clinically Based conceptualization of frailty 160,450,597. Integrating the clinical manifestations of frailty with the hallmarks/pillars of aging results in the current conceptualization. Mitochondrial dysfunction, epigenetic alterations, and oxidative stress represent cellular/molecular factors that contribute to three central physiological systems that promote the Frailty Phenotype. The mitochondrial dysfunction accounts for a reduction in the efficiency of oxidative phosphorylation and a reduction in the energy production generating long‐term exhaustion/fatigue. Epigenetic alterations such as DNA methylation and histone modifications are triggered by chronological aging and environmental factors, influencing pathways of health and longevity. Lastly, oxidative stress refers to excessive production of reactive oxygen species (ROS) that leads to cell and tissue damage. The metabolic system represents pathways that are centrally mediated by nutrient‐sensing mechanisms, in which the glucose metabolism, insulin signaling cascade as well as AMP‐activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD+) are pivotal players. The stress‐response system is mainly influenced by the hypothalamic‐pituitary‐adrenal (HPA) axis, the autonomic nervous system, and by the immune system. The cognitive and muscular declines, here illustrated by the neuromuscular category, are driven by tissue waste and dysfunction, leading to weight loss, weakness, fatigue, low activity, and slow gait at the organismal level. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 5. Inflammaging. The biology underlying inflammaging is multifactorial. The mechanisms that contribute to inappropriate inflammatory responses and ultimately low‐level chronic inflammaging include cellular senescence, mitochondrial dysfunction, oxidative stress, visceral adiposity, gut dysbiosis, genetic predisposition, and epigenetics factors such as microRNAs. Potential mediators contributing to the chronic inflammation have both local and systemic impacts that likely promote physical decline. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 6. Caloric restriction. Caloric restriction is the most well‐established longevity‐modulating intervention. Importantly, dietary restriction whether caloric (protein, carbohydrates, fat), intermittent feeding, or fasting improves health by decreasing morbidities that are associated with aging including frailty. It does so through alterations in energy restriction pathways. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 7. Sarcopenia. Sarcopenia is the natural event that is characterized by muscle loss and function. At the muscle fiber level, it is observed as a reduction in the fiber quality, size, and number. There is also a reduction in the number and quality of satellite cells, which are stem cells that promote skeletal muscle homeostasis and repair. In the muscle cell, the sarcopenic process is not only driven by increased protein degradation and decreased synthesis, but also by oxidative stress, insulin resistance, ectopic fat accumulation, and inflammation. Multiple signaling pathways provide avenues for therapeutic intervention. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.


Figure 8. Physiological systems promoting frailty. Frailty involves a multiple organ network that deteriorates with age and features a decline in functional reserves of many physiological systems. There are common impaired responses observed in many organs of the individual with frailty including inflammation, oxidative stress, ectopic fat accumulation, and insulin resistance. The liver is a central player in metabolism and has thus a key role in the aging process. In frailty, there is an increase in de novo lipogenesis that refers to the biochemical synthesis of fatty acids from the carbohydrate catabolism, boosting ectopic fat accumulation. The fatty liver, combined with inflammation and oxidative stress, promotes hepatocyte injury, facilitating fibrosis (collagen production), stem cell activation, and even cancer development. Muscle is also central to the biology of frailty and is the main organ system contributing to the Frailty Phenotype as muscle mass loss and protein degradation trigger weakness, slowness, and weight loss. As compared to subcutaneous adiposity, visceral adiposity is the most detrimental to health due to its pro‐inflammatory profile. The increased inflammation, ectopic fat accumulation, and oxidative stress are all risk factors to cardiovascular events by facilitating endothelial dysfunction, aortic stiffness, and clotting. On top of that, increased visceral adiposity and hepatic de novo lipogenesis promote dyslipidemia, which also contributes to cardiovascular dysfunction. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.
References
 1.Aas SN, Hamarsland H, Cumming KT, Rognlien SH, Aase OJ, Nordseth M, Karsrud S, Godager S, Tømmerbakke D, Handegard V, Raastad T. The impact of age and frailty on skeletal muscle autophagy markers and specific strength: A cross‐sectional comparison. Exp Gerontol 125: 110687, 2019.
 2.Abbasi F, Brown BW, Lamendola C, McLaughlin T, Reaven GM. Relationship between obesity, insulin resistance, and coronary heart disease risk. J Am Coll Cardiol 40: 937‐943, 2002.
 3.Ackert‐Bicknell CL, Anderson LC, Sheehan S, Hill WG, Chang B, Churchill GA, Chesler EJ, Korstanje R, Peters LL. Aging research using mouse models. Curr Protoc Mouse Biol 5: 95‐133, 2015.
 4.Addison O, Drummond MJ, LaStayo PC, Dibble LE, Wende AR, McClain DA, Marcus RL. Intramuscular fat and inflammation differ in older adults: The impact of frailty and inactivity. J Nutr Health Aging 18: 532‐538, 2014.
 5.Adelnia F, Urbanek J, Osawa Y, Shardell M, Brennan NA, Fishbein KW, Spencer RG, Simonsick EM, Schrack JA, Ferrucci L. Moderate‐to‐vigorous physical activity is associated with higher muscle oxidative capacity in older adults. J Am Geriatr Soc 67: 1695‐1699, 2019.
 6.Afilalo J, Alexander KP, Mack MJ, Maurer MS, Green P, Allen LA, Popma JJ, Ferrucci L, Forman DE. Frailty assessment in the cardiovascular care of older adults. J Am Coll Cardiol 63: 747‐762, 2014.
 7.Aguirre LE, Villareal DT. Physical exercise as therapy for frailty. Nestle Nutr Inst Workshop Ser 83: 83‐92, 2015.
 8.Akki A, Yang H, Gupta A, Chacko VP, Yano T, Leppo MK, Steenbergen C, Walston J, Weiss RG. Skeletal muscle ATP kinetics are impaired in frail mice. Age (Dordr) 36: 21‐30, 2014.
 9.Al Saedi A, Gunawardene P, Bermeo S, Vogrin S, Boersma D, Phu S, Singh L, Suriyaarachchi P, Duque G. Lamin A expression in circulating osteoprogenitors as a potential biomarker for frailty: The Nepean Osteoporosis and Frailty (NOF) Study. Exp Gerontol 102: 69‐75, 2018.
 10.Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world‐wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23: 469‐480, 2006.
 11.Alway SE, Mohamed JS, Myers MJ. Mitochondria initiate and regulate sarcopenia. Exerc Sport Sci Rev 45: 58‐69, 2017.
 12.Anderson DE, Quinn E, Parker E, Allaire BT, Muir JW, Rubin CT, Magaziner J, Hannan MT, Bouxsein ML, Kiel DP. Associations of computed tomography‐based trunk muscle size and density with balance and falls in older adults. J Gerontol A Biol Sci Med Sci 71: 811‐816, 2016.
 13.Andrade TA, Evangelista AF, Campos AH, Poles WA, Borges NM, Camillo CM, Soares FA, Vassallo J, Paes RP, Zerbini MC, Scapulatempo C, Alves AC, Young KH, Colleoni GW. A microRNA signature profile in EBV+ diffuse large B‐cell lymphoma of the elderly. Oncotarget 5: 11813‐11826, 2014.
 14.Andreux PA, van Diemen MPJ, Heezen MR, Auwerx J, Rinsch C, Groeneveld GJ, Singh A. Mitochondrial function is impaired in the skeletal muscle of pre‐frail elderly. Sci Rep 8: 8548, 2018.
 15.Andrew MK, Mitnitski AB, Rockwood K. Social vulnerability, frailty and mortality in elderly people. PLoS One 3: e2232, 2008.
 16.Angioni D, Macaron T, Takeda C, Sourdet S, Cesari M, Virecoulon Giudici K, Raffin J, Lu WH, Delrieu J, Touchon J, Rolland Y, de Souto Barreto P, Vellas B. Can we distinguish age‐related frailty from frailty related to diseases: Data from the MAPT study. J Nutr Health Aging 24: 1144‐1151, 2020.
 17.Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer‐prone mice. Am J Pathol 176: 2092‐2097, 2010.
 18.Antoch MP, Wrobel M, Kuropatwinski KK, Gitlin I, Leonova KI, Toshkov I, Gleiberman AS, Hutson AD, Chernova OB, Gudkov AV. Physiological Frailty Index (PFI): Quantitative in‐life estimate of individual biological age in mice. Aging (Albany NY) 9: 615‐626, 2017.
 19.Applegate WB, Pressel S, Wittes J, Luhr J, Shekelle RB, Camel GH, Greenlick MR, Hadley E, Moye L, Perry HM. Impact of the treatment of isolated systolic hypertension on behavioral variables. Results from the systolic hypertension in the elderly program. Arch Intern Med 154: 2154‐2160, 1994.
 20.Aprahamian I, Xue QL. Shaping the next steps of research on frailty: Challenges and opportunities. BMC Geriatr 21: 432, 2021.
 21.Aramillo Irizar P, Schäuble S, Esser D, Groth M, Frahm C, Priebe S, Baumgart M, Hartmann N, Marthandan S, Menzel U, Müller J, Schmidt S, Ast V, Caliebe A, König R, Krawczak M, Ristow M, Schuster S, Cellerino A, Diekmann S, Englert C, Hemmerich P, Sühnel J, Guthke R, Witte OW, Platzer M, Ruppin E, Kaleta C. Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly. Nat Commun 9: 327, 2018.
 22.Artaza‐Artabe I, Sáez‐López P, Sánchez‐Hernández N, Fernández‐Gutierrez N, Malafarina V. The relationship between nutrition and frailty: Effects of protein intake, nutritional supplementation, vitamin D and exercise on muscle metabolism in the elderly. A systematic review. Maturitas 93: 89‐99, 2016.
 23.Arts MH, Collard RM, Comijs HC, Naudé PJ, Risselada R, Naarding P, Oude Voshaar RC. Relationship between physical frailty and low‐grade inflammation in late‐life depression. J Am Geriatr Soc 63: 1652‐1657, 2015.
 24.Arum O, Rasche ZA, Rickman DJ, Bartke A. Prevention of neuromusculoskeletal frailty in slow‐aging ames dwarf mice: Longitudinal investigation of interaction of longevity genes and caloric restriction. PLoS One 8: e72255, 2013.
 25.Arum O, Rickman DJ, Kopchick JJ, Bartke A. The slow‐aging growth hormone receptor/binding protein gene‐disrupted (GHR‐KO) mouse is protected from aging‐resultant neuromusculoskeletal frailty. Age (Dordr) 36: 117‐127, 2014.
 26.Ashar FN, Moes A, Moore AZ, Grove ML, Chaves PHM, Coresh J, Newman AB, Matteini AM, Bandeen‐Roche K, Boerwinkle E, Walston JD, Arking DE. Association of mitochondrial DNA levels with frailty and all‐cause mortality. J Mol Med (Berl) 93: 177‐186, 2015.
 27.Austad SN, Allison DB. Perspectives in aging: Nutritional and energetic interventions. Exp Gerontol 86: 1‐3, 2016.
 28.Bandeen‐Roche K, Seplaki CL, Huang J, Buta B, Kalyani RR, Varadhan R, Xue QL, Walston JD, Kasper JD. Frailty in older adults: A nationally representative profile in the United States. J Gerontol A Biol Sci Med Sci 70: 1427‐1434, 2015.
 29.Bannister CA, Holden SE, Jenkins‐Jones S, Morgan CL, Halcox JP, Schernthaner G, Mukherjee J, Currie CJ. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non‐diabetic controls. Diabetes Obes Metab 16: 1165‐1173, 2014.
 30.Banzato T, Franzo G, Di Maggio R, Nicoletto E, Burti S, Cesari M, Canevelli M. A Frailty Index based on clinical data to quantify mortality risk in dogs. Sci Rep 9: 16749, 2019.
 31.Barnes BR, Long YC, Steiler TL, Leng Y, Galuska D, Wojtaszewski JF, Andersson L, Zierath JR. Changes in exercise‐induced gene expression in 5′‐AMP‐activated protein kinase gamma3‐null and gamma3 R225Q transgenic mice. Diabetes 54: 3484‐3489, 2005.
 32.Barnes PJ, Bonini S, Seeger W, Belvisi MG, Ward B, Holmes A. Barriers to new drug development in respiratory disease. Eur Respir J 45: 1197‐1207, 2015.
 33.Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: A cross‐sectional study. Lancet 380: 37‐43, 2012.
 34.Barreto G, Huang TT, Giffard RG. Age‐related defects in sensorimotor activity, spatial learning, and memory in C57BL/6 mice. J Neurosurg Anesthesiol 22: 214‐219, 2010.
 35.Bartke A, Brown‐Borg H. Mutations affecting mammalian aging: GH and GHR vs IGF‐1 and insulin. Front Genet 12: 667355, 2021.
 36.Barton ER, DeMeo J, Lei H. The insulin‐like growth factor (IGF)‐I E‐peptides are required for isoform‐specific gene expression and muscle hypertrophy after local IGF‐I production. J Appl Physiol (1985) 108: 1069, 2010‐1076.
 37.Barzilay JI, Blaum C, Moore T, Xue QL, Hirsch CH, Walston JD, Fried LP. Insulin resistance and inflammation as precursors of frailty: The Cardiovascular Health Study. Arch Intern Med 167: 635‐641, 2007.
 38.Bastos‐Barbosa RG, Ferriolli E, Coelho EB, Moriguti JC, Nobre F, Lima NK, da Costa Lima NK. Association of frailty syndrome in the elderly with higher blood pressure and other cardiovascular risk factors. Am J Hypertens 25: 1156‐1161, 2012.
 39.Batsis JA, Villareal DT. Sarcopenic obesity in older adults: Aetiology, epidemiology and treatment strategies. Nat Rev Endocrinol 14: 513‐537, 2018.
 40.Baumann C, Kwak D, Thompson L. Phenotypic frailty assessment in mice: Development, discoveries, and experimental considerations. Physiology 35: 405‐414, 2020.
 41.Baumann CW, Kwak D, Thompson L. Sex‐specific components of frailty in C57BL/6 mice. Aging (Albany NY) 11: 5206‐5214, 2019.
 42.Baumann CW, Kwak D, Thompson LV. Assessing onset, prevalence and survival in mice using a frailty phenotype. Aging (Albany NY) 10: 4042‐4053, 2018.
 43.Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, Ross RR, Garry PJ, Lindeman RD. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 147: 755‐763, 1998.
 44.Baylis D, Bartlett DB, Syddall HE, Ntani G, Gale CR, Cooper C, Lord JM, Sayer AA. Immune‐endocrine biomarkers as predictors of frailty and mortality: A 10‐year longitudinal study in community‐dwelling older people. Age (Dordr) 35: 963‐971, 2013.
 45.Beard JR, Officer A, de Carvalho IA, Sadana R, Pot AM, Michel JP, Lloyd‐Sherlock P, Epping‐Jordan JE, Peeters GMEE, Mahanani WR, Thiyagarajan JA, Chatterji S. The World report on ageing and health: A policy framework for healthy ageing. Lancet 387: 2145‐2154, 2016.
 46.Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, Rossi DJ. Proliferation‐dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12: 413‐425, 2013.
 47.Bellantuono I, de Cabo R, Ehninger D, Di Germanio C, Lawrie A, Miller J, Mitchell SJ, Navas‐Enamorado I, Potter PK, Tchkonia T, Trejo JL, Lamming DW. A toolbox for the longitudinal assessment of healthspan in aging mice. Nat Protoc 15: 540‐574, 2020.
 48.Belsky DW, Huffman KM, Pieper CF, Shalev I, Kraus WE. Change in the rate of biological aging in response to caloric restriction: CALERIE biobank analysis. J Gerontol A Biol Sci Med Sci 73: 4‐10, 2017.
 49.Ben‐Avraham D, Govindaraju DR, Budagov T, Fradin D, Durda P, Liu B, Ott S, Gutman D, Sharvit L, Kaplan R, Bougnères P, Reiner A, Shuldiner AR, Cohen P, Barzilai N, Atzmon G. The GH receptor exon 3 deletion is a marker of male‐specific exceptional longevity associated with increased GH sensitivity and taller stature. Sci Adv 3: e1602025, 2017.
 50.Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: Linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16: 593‐610, 2015.
 51.Bennett C, de Cabo R, Pasquina PF, Smith WK. White paper on a national investment in Geroscience. 2021. https://www.geroscience.health.
 52.Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development 141: 4206‐4218, 2014.
 53.Bird A. Perceptions of epigenetics. Nature 447: 396‐398, 2007.
 54.Blackwell BN, Bucci TJ, Hart RW, Turturro A. Longevity, body weight, and neoplasia in ad libitum‐fed and diet‐restricted C57BL6 mice fed NIH‐31 open formula diet. Toxicol Pathol 23: 570‐582, 1995.
 55.Blagosklonny MV. An anti‐aging drug today: From senescence‐promoting genes to anti‐aging pill. Drug Discov Today 12: 218‐224, 2007.
 56.Blake DJ, Weir A, Newey SE, Davies KE. Function and genetics of dystrophin and dystrophin‐related proteins in muscle. Physiol Rev 82: 291‐329, 2002.
 57.Blau HM, Cosgrove BD, Ho AT. The central role of muscle stem cells in regenerative failure with aging. Nat Med 21: 854‐862, 2015.
 58.Bonafe L, Dermitzakis ET, Unger S, Greenberg CR, Campos‐Xavier BA, Zankl A, Ucla C, Antonarakis SE, Superti‐Furga A, Reymond A. Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. PLoS Genet 1: e47, 2005.
 59.Bonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 6: 25‐39, 2013.
 60.Bonkowski MS, Sinclair DA. Slowing ageing by design: The rise of NAD. Nat Rev Mol Cell Biol 17: 679‐690, 2016.
 61.Booth LN, Brunet A. The aging epigenome. Mol Cell 62: 728‐744, 2016.
 62.Bouché M, Muñoz‐Cánoves P, Rossi F, Coletti D. Inflammation in muscle repair, aging, and myopathies. Biomed Res Int 2014: 821950, 2014.
 63.Bouillon K, Batty GD, Hamer M, Sabia S, Shipley MJ, Britton A, Singh‐Manoux A, Kivimäki M. Cardiovascular disease risk scores in identifying future frailty: The Whitehall II Prospective Cohort Study. Heart 99: 737‐742, 2013.
 64.Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317: 807‐810, 2007.
 65.Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest 123: 951‐957, 2013.
 66.Braun TP, Marks DL. The regulation of muscle mass by endogenous glucocorticoids. Front Physiol 6: 12, 2015.
 67.Breitling LP, Saum KU, Perna L, Schöttker B, Holleczek B, Brenner H. Frailty is associated with the epigenetic clock but not with telomere length in a German cohort. Clin Epigenetics 8: 21, 2016.
 68.Brivio P, Paladini MS, Racagni G, Riva MA, Calabrese F, Molteni R. From healthy aging to frailty: In search of the underlying mechanisms. Curr Med Chem 26: 3685‐3701, 2019.
 69.Brown‐Borg HM. Hormonal control of aging in rodents: The somatotropic axis. Mol Cell Endocrinol 299: 64‐71, 2009.
 70.Brown‐Borg HM, Rakoczy SG, Sharma S, Bartke A. Long‐living growth hormone receptor knockout mice: Potential mechanisms of altered stress resistance. Exp Gerontol 44: 10‐19, 2009.
 71.Bryda EC. The Mighty Mouse: The impact of rodents on advances in biomedical research. Mo Med 110: 207‐211, 2013.
 72.Buckinx F, Rolland Y, Reginster JY, Ricour C, Petermans J, Bruyère O. Burden of frailty in the elderly population: Perspectives for a public health challenge. Arch Public Health 73: 19, 2015.
 73.Cabreiro F, Au C, Leung KY, Vergara‐Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene ND, Gems D. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153: 228‐239, 2013.
 74.Calderón‐Larrañaga A, Vetrano DL, Onder G, Gimeno‐Feliu LA, Coscollar‐Santaliestra C, Carfí A, Pisciotta MS, Angleman S, Melis RJF, Santoni G, Mangialasche F, Rizzuto D, Welmer AK, Bernabei R, Prados‐Torres A, Marengoni A, Fratiglioni L. Assessing and measuring chronic multimorbidity in the older population: A proposal for its operationalization. J Gerontol A Biol Sci Med Sci 72: 1417‐1423, 2017.
 75.Calvani R, Picca A, Marini F, Biancolillo A, Cesari M, Pesce V, Lezza AMS, Bossola M, Leeuwenburgh C, Bernabei R, Landi F, Marzetti E. The “BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons” (BIOSPHERE) study: Rationale, design and methods. Eur J Intern Med 56: 19‐25, 2018.
 76.Camacho‐Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN. CD38 dictates age‐related NAD decline and mitochondrial dysfunction through an SIRT3‐dependent mechanism. Cell Metab 23: 1127‐1139, 2016.
 77.Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all‐cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta‐analysis. Ageing Res Rev 40: 31‐44, 2017.
 78.Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol 75: 685‐705, 2013.
 79.Caplan AI, Correa D. The MSC: An injury drugstore. Cell Stem Cell 9: 11‐15, 2011.
 80.Cardoso AL, Fernandes A, Aguilar‐Pimentel JA, de Angelis MH, Guedes JR, Brito MA, Ortolano S, Pani G, Athanasopoulou S, Gonos ES, Schosserer M, Grillari J, Peterson P, Tuna BG, Dogan S, Meyer A, van Os R, Trendelenburg AU. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age‐related diseases. Ageing Res Rev 47: 214‐277, 2018.
 81.Carnio S, LoVerso F, Baraibar MA, Longa E, Khan MM, Maffei M, Reischl M, Canepari M, Loefler S, Kern H, Blaauw B, Friguet B, Bottinelli R, Rudolf R, Sandri M. Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep 8: 1509‐1521, 2014.
 82.Carter CS, Justice JN, Thompson L. Lipotoxicity, aging, and muscle contractility: Does fiber type matter? Geroscience 41: 297‐308, 2019.
 83.Castrejón‐Pérez RC, Gutiérrez‐Robledo LM, Cesari M, Pérez‐Zepeda MU. Diabetes mellitus, hypertension and frailty: A population‐based, cross‐sectional study of Mexican older adults. Geriatr Gerontol Int 17: 925‐930, 2017.
 84.Cencioni C, Heid J, Krepelova A, Rasa SMM, Kuenne C, Guenther S, Baumgart M, Cellerino A, Neri F, Spallotta F, Gaetano C. Aging triggers H3K27 trimethylation hoarding in the chromatin of Nothobranchius furzeri skeletal muscle. Cells 8: 1169, 2019.
 85.Cermak NM, Res PT, de Groot LC, Saris WH, van Loon LJ. Protein supplementation augments the adaptive response of skeletal muscle to resistance‐type exercise training: A meta‐analysis. Am J Clin Nutr 96: 1454‐1464, 2012.
 86.Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA, Li W, Leoni V, Schon EA, Dantzer F, Auwerx J, Viscomi C, Zeviani M. NAD(+)‐dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab 19: 1042‐1049, 2014.
 87.Cesari M, Gambassi G, van Kan GA, Vellas B. The frailty phenotype and the frailty index: Different instruments for different purposes. Age Ageing 43: 10‐12, 2014.
 88.Cesari M, Landi F, Calvani R, Cherubini A, Di Bari M, Kortebein P, Del Signore S, Le Lain R, Vellas B, Pahor M, Roubenoff R, Bernabei R, Marzetti E, SPRINTT Consortium. Rationale for a preliminary operational definition of physical frailty and sarcopenia in the SPRINTT trial. Aging Clin Exp Res 29: 81‐88, 2017.
 89.Chabi B, Ljubicic V, Menzies KJ, Huang JH, Saleem A, Hood DA. Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging Cell 7: 2‐12, 2008.
 90.Chakkalakal JV, Jones KM, Basson MA, Brack AS. The aged niche disrupts muscle stem cell quiescence. Nature 490: 355‐360, 2012.
 91.Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5: e201, 2007.
 92.Chandel NS, Jasper H, Ho TT, Passegué E. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol 18: 823‐832, 2016.
 93.Chaves PH, Semba RD, Leng SX, Woodman RC, Ferrucci L, Guralnik JM, Fried LP. Impact of anemia and cardiovascular disease on frailty status of community‐dwelling older women: The Women's Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci 60: 729‐735, 2005.
 94.Cheng MH, Chang SF. Frailty as a risk factor for falls among community dwelling people: Evidence from a meta‐analysis. J Nurs Scholarsh 49: 529‐536, 2017.
 95.Chew J, Tay L, Lim JP, Leung BP, Yeo A, Yew S, Ding YY, Lim WS. Serum myostatin and IGF‐1 as gender‐specific biomarkers of frailty and low muscle mass in community‐dwelling older adults. J Nutr Health Aging 23: 979‐986, 2019.
 96.Chhetri JK, Zheng Z, Xu X, Ma C, Chan P. The prevalence and incidence of frailty in pre‐diabetic and diabetic community‐dwelling older population: Results from Beijing Longitudinal Study of Aging II (BLSA‐II). BMC Geriatr 17: 47, 2017.
 97.Childers DK, Allison DB. The 'obesity paradox': A parsimonious explanation for relations among obesity, mortality rate and aging? Int J Obes (Lond) 34: 1231‐1238, 2010.
 98.Cho K, Chung JY, Cho SK, Shin HW, Jang IJ, Park JW, Yu KS, Cho JY. Antihyperglycemic mechanism of metformin occurs via the AMPK/LXRα/POMC pathway. Sci Rep 5: 8145, 2015.
 99.Choe YR, Jeong JR, Kim YP. Grip strength mediates the relationship between muscle mass and frailty. J Cachexia Sarcopenia Muscle 11: 441‐451, 2020.
 100.Choi J, Ahn A, Kim S, Won CW. Global prevalence of physical frailty by Fried's criteria in community‐dwelling elderly with national population‐based surveys. J Am Med Dir Assoc 16: 548‐550, 2015.
 101.Choi S, Reiter DA, Shardell M, Simonsick EM, Studenski S, Spencer RG, Fishbein KW, Ferrucci L. 31p magnetic resonance spectroscopy assessment of muscle bioenergetics as a predictor of gait speed in the Baltimore Longitudinal Study of Aging. J Gerontol A Biol Sci Med Sci 71: 1638‐1645, 2016.
 102.Chrousos GP. The hypothalamic‐pituitary‐adrenal axis and immune‐mediated inflammation. N Engl J Med 332: 1351‐1362, 1995.
 103.Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol 5: 374‐381, 2009.
 104.Cigolle CT, Ofstedal MB, Tian Z, Blaum CS. Comparing models of frailty: The Health and Retirement Study. J Am Geriatr Soc 57: 830‐839, 2009.
 105.Clegg A, Hassan‐Smith Z. Frailty and the endocrine system. Lancet Diabetes Endocrinol 6: 743‐752, 2018.
 106.Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 381: 752‐762, 2013.
 107.Coelho‐Júnior HJ, Calvani R, Picca A, Gonçalves IO, Landi F, Bernabei R, Cesari M, Uchida MC, Marzetti E. Protein‐related dietary parameters and frailty status in older community‐dwellers across different frailty instruments. Nutrients 12, 2020.
 108.Coelho‐Junior HJ, Marzetti E, Picca A, Cesari M, Uchida MC, Calvani R. Protein intake and frailty: A matter of quantity, quality, and timing. Nutrients 12: 2915, 2020.
 109.Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalence of frailty in community‐dwelling older persons: A systematic review. J Am Geriatr Soc 60: 1487‐1492, 2012.
 110.Collerton J, Gautrey HE, van Otterdijk SD, Davies K, Martin‐Ruiz C, von Zglinicki T, Kirkwood TB, Jagger C, Mathers JC, Strathdee G. Acquisition of aberrant DNA methylation is associated with frailty in the very old: Findings from the Newcastle 85+ Study. Biogerontology 15: 317‐328, 2014.
 111.Collerton J, Martin‐Ruiz C, Davies K, Hilkens CM, Isaacs J, Kolenda C, Parker C, Dunn M, Catt M, Jagger C, von Zglinicki T, Kirkwood TB. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: Cross‐sectional findings from the Newcastle 85+ Study. Mech Ageing Dev 133: 456‐466, 2012.
 112.Collino S, Martin FP, Karagounis LG, Horcajada MN, Moco S, Franceschi C, Kussmann M, Offord E. Reprint of: Musculoskeletal system in the old age and the demand for healthy ageing biomarkers. Mech Ageing Dev 136‐137: 94‐100, 2014.
 113.Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325: 201‐204, 2009.
 114.Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age‐related and all‐cause mortality in rhesus monkeys. Nat Commun 5: 3557, 2014.
 115.Conte M, Martucci M, Mosconi G, Chiariello A, Cappuccilli M, Totti V, Santoro A, Franceschi C, Salvioli S. GDF15 plasma level is inversely associated with level of physical activity and correlates with markers of inflammation and muscle weakness. Front Immunol 11: 915, 2020.
 116.Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3: 403‐416, 2006.
 117.Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence‐associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol 5: 99‐118, 2010.
 118.Correia‐Melo C, Birch J, Fielder E, Rahmatika D, Taylor J, Chapman J, Lagnado A, Carroll BM, Miwa S, Richardson G, Jurk D, Oakley F, Mann J, Mann DA, Korolchuk VI, Passos JF. Rapamycin improves healthspan but not inflammaging in nfκb1. Aging Cell 18: e12882, 2019.
 119.Costamagna D, Costelli P, Sampaolesi M, Penna F. Role of inflammation in muscle homeostasis and myogenesis. Mediators Inflamm 2015: 805172, 2015.
 120.Cruz‐Jentoft A, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer A, Schneider S, Sieber C, Topinkova E, Vandewoude M, Visser M, Zamboni M. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 48: 16‐31, 2018.
 121.Cruz‐Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinková E, Vandewoude M, Zamboni M. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39: 412‐423, 2010.
 122.Da Mata FA, Pereira PP, Andrade KR, Figueiredo AC, Silva MT, Pereira MG. Prevalence of frailty in Latin America and the Caribbean: A systematic review and meta‐analysis. PLoS One 11: e0160019, 2016.
 123.Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: From molecular mechanisms to significance in human health and disease. Antioxid Redox Signal 16: 1492‐1526, 2012.
 124.Dai DF, Hsieh EJ, Liu Y, Chen T, Beyer RP, Chin MT, MacCoss MJ, Rabinovitch PS. Mitochondrial proteome remodelling in pressure overload‐induced heart failure: The role of mitochondrial oxidative stress. Cardiovasc Res 93: 79‐88, 2012.
 125.Dai DF, Rabinovitch PS, Ungvari Z. Mitochondria and cardiovascular aging. Circ Res 110: 1109‐1124, 2012.
 126.Dankner R, Chetrit A, Shanik MH, Raz I, Roth J. Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up. Diabetes Metab Res Rev 28: 618‐624, 2012.
 127.Dardevet D, Rémond D, Peyron MA, Papet I, Savary‐Auzeloux I, Mosoni L. Muscle wasting and resistance of muscle anabolism: The “anabolic threshold concept” for adapted nutritional strategies during sarcopenia. ScientificWorldJournal 2012: 269531, 2012.
 128.Darvin K, Randolph A, Ovalles S, Halade D, Breeding L, Richardson A, Espinoza SE. Plasma protein biomarkers of the geriatric syndrome of frailty. J Gerontol A Biol Sci Med Sci 69: 182‐186, 2014.
 129.Davies B, García F, Ara I, Artalejo FR, Rodriguez‐Mañas L, Walter S. Relationship between sarcopenia and frailty in the Toledo Study of Healthy Aging: A population based cross‐sectional study. J Am Med Dir Assoc 19: 282‐286, 2018.
 130.Davies KE, Nowak KJ. Molecular mechanisms of muscular dystrophies: Old and new players. Nat Rev Mol Cell Biol 7: 762‐773, 2006.
 131.Davis MM, Tato CM, Furman D. Systems immunology: Just getting started. Nat Immunol 18: 725‐732, 2017.
 132.De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol 80: 219‐227, 2006.
 133.de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15: 522‐530, 2016.
 134.de Souto, Barreto P, Guyonnet S, Ader I, Andrieu S, Casteilla L, Davezac N, Dray C, Fazilleau N, Gourdy P, Liblau R, Parini A, Payoux P, Pénicaud L, Rampon C, Rolland Y, Valet P, Vergnolle N, Vellas B. The INSPIRE Research Initiative: A program for GeroScience and Healthy Aging Research going from animal models to humans and the healthcare system. J Frailty Aging 10: 86‐93, 2021.
 135.Deepa SS, Bhaskaran S, Espinoza S, Brooks SV, McArdle A, Jackson MJ, Van Remmen H, Richardson A. A new mouse model of frailty: The Cu/Zn superoxide dismutase knockout mouse. Geroscience 39: 187‐198, 2017.
 136.Demontiero O, Gunawardene P, Duque G. Postoperative prevention of falls in older adults with fragility fractures. Clin Geriatr Med 30: 333‐347, 2014.
 137.Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: A review. Eur J Intern Med 31: 3‐10, 2016.
 138.Després JP, Lemieux I, Alméras N. Contribution of CB1 blockade to the management of high‐risk abdominal obesity. Int J Obes (Lond) 30 Suppl 1: S44‐S52, 2006.
 139.Doi T, Makizako H, Tsutsumimoto K, Hotta R, Nakakubo S, Makino K, Suzuki T, Shimada H. Association between insulin‐like growth factor and frailty among older adults. J Nutr Health Aging 22: 68‐72, 2018.
 140.Drummond MJ, Addison O, Brunker L, Hopkins PN, McClain DA, LaStayo PC, Marcus RL. Downregulation of E3 ubiquitin ligases and mitophagy‐related genes in skeletal muscle of physically inactive, frail older women: A cross‐sectional comparison. J Gerontol A Biol Sci Med Sci 69: 1040‐1048, 2014.
 141.Drummond MJ, McCarthy JJ, Fry CS, Esser KA, Rasmussen BB. Aging differentially affects human skeletal muscle microRNA expression at rest and after an anabolic stimulus of resistance exercise and essential amino acids. Am J Physiol Endocrinol Metab 295: E1333‐E1340, 2008.
 142.Duarte N, Teixeira L, Ribeiro O, Paúl C. Frailty phenotype criteria in centenarians: Findings from the Oporto Centenarian Study. Eur Geriatr Med 5: 371‐376, 2014.
 143.Dunlap KR, Steiner JL, Rossetti ML, Kimball SR, Gordon BS. A clinically relevant decrease in contractile force differentially regulates control of glucocorticoid receptor translocation in mouse skeletal muscle. J Appl Physiol (1985) 130: 1052‐1063, 2021.
 144.Effros RB. The silent war of CMV in aging and HIV infection. Mech Ageing Dev 158: 46‐52, 2016.
 145.Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ, Huang TT. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24: 367‐380, 2005.
 146.Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, Cartwright DM, Oakey L, Burley CV, Jenkinson N, Wilson M, Lucas SJE, Akerman I, Seabright A, Lai YC, Tennant DA, Nightingale P, Wallis GA, Manolopoulos KN, Brenner C, Philp A, Lavery GG. Nicotinamide riboside augments the aged human skeletal muscle NAD. Cell Rep 28: 1717‐1728.e1716, 2019.
 147.ElSharawy A, Keller A, Flachsbart F, Wendschlag A, Jacobs G, Kefer N, Brefort T, Leidinger P, Backes C, Meese E, Schreiber S, Rosenstiel P, Franke A, Nebel A. Genome‐wide miRNA signatures of human longevity. Aging Cell 11: 607‐616, 2012.
 148.Ensrud KE, Ewing SK, Cawthon PM, Fink HA, Taylor BC, Cauley JA, Dam TT, Marshall LM, Orwoll ES, Cummings SR, Osteoporotic Fractures in Men Research Group. A comparison of frailty indexes for the prediction of falls, disability, fractures, and mortality in older men. J Am Geriatr Soc 57: 492‐498, 2009.
 149.Espinoza SE, Jung I, Hazuda H. Frailty transitions in the San Antonio Longitudinal Study of Aging. J Am Geriatr Soc 60: 652‐660, 2012.
 150.Espinoza SE, Musi N, Wang CP, Michalek J, Orsak B, Romo T, Powers B, Conde A, Moris M, Bair‐Kelps D, Li Y, Ganapathy V, Jergensen TE, Kelly LC, Jiwani R. Rationale and study design of a randomized clinical trial of metformin to prevent frailty in older adults with prediabetes. J Gerontol A Biol Sci Med Sci 75: 102‐109, 2020.
 151.Espinoza SE, Quiben M, Hazuda HP. Distinguishing comorbidity, disability, and frailty. Curr Geriatr Rep 7: 201‐209, 2018.
 152.Evans WJ, Paolisso G, Abbatecola AM, Corsonello A, Bustacchini S, Strollo F, Lattanzio F. Frailty and muscle metabolism dysregulation in the elderly. Biogerontology 11: 527‐536, 2010.
 153.Fahlström A, Yu Q, Ulfhake B. Behavioral changes in aging female C57BL/6 mice. Neurobiol Aging 32: 1868‐1880, 2011.
 154.Fazelzadeh P, Hangelbroek RW, Tieland M, de Groot LC, Verdijk LB, van Loon LJ, Smilde AK, Alves RD, Vervoort J, Müller M, van Duynhoven JP, Boekschoten MV. The muscle metabolome differs between healthy and frail older adults. J Proteome Res 15: 499‐509, 2016.
 155.Feng Z, Lugtenberg M, Franse C, Fang X, Hu S, Jin C, Raat H. Risk factors and protective factors associated with incident or increase of frailty among community‐dwelling older adults: A systematic review of longitudinal studies. PLoS One 12: e0178383, 2017.
 156.Feridooni HA, Sun MH, Rockwood K, Howlett SE. Reliability of a frailty index based on the clinical assessment of health deficits in male C57BL/6J mice. J Gerontol A Biol Sci Med Sci 70: 686‐693, 2015.
 157.Ferrari E, Magri F. Role of neuroendocrine pathways in cognitive decline during aging. Ageing Res Rev 7: 225‐233, 2008.
 158.Ferrucci L, Fabbri E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 15: 505‐522, 2018.
 159.Ferrucci L, Fabbri E, Walston JD. Frailty. In: Halter JB, Ouslander JG, Studenski S, High KP, Asthana S, Supiano MA, Ritchie C, editors. Hazzard's Geriatric Medicine and Gerontology (7th ed). New York, NY: McGraw‐Hill Education, 2017.
 160.Ferrucci L, Gonzalez‐Freire M, Fabbri E, Simonsick E, Tanaka T, Moore Z, Salimi S, Sierra F, de Cabo R. Measuring biological aging in humans: A quest. Aging Cell 19: e13080, 2020.
 161.Ferrucci L, Zampino M. A mitochondrial root to accelerated ageing and frailty. Nat Rev Endocrinol 16: 133‐134, 2020.
 162.Fielder E, Weigand M, Agneessens J, Griffin B, Parker C, Miwa S, von Zglinicki T. Sublethal whole‐body irradiation causes progressive premature frailty in mice. Mech Ageing Dev 180: 63‐69, 2019.
 163.Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of mitochondrial dysfunction and fatigue: A review of the literature. BBA Clin 1: 12‐23, 2014.
 164.Fischer KE, Hoffman JM, Sloane LB, Gelfond JA, Soto VY, Richardson AG, Austad SN. A cross‐sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging (Albany NY) 8: 2370‐2391, 2016.
 165.Flanagan EW, Most J, Mey JT, Redman LM. Calorie restriction and aging in humans. Annu Rev Nutr 40: 105‐133, 2020.
 166.Flegal KM, Kalantar‐Zadeh K. Overweight, mortality and survival. Obesity (Silver Spring) 21: 1744‐1745, 2013.
 167.Florian MC, Klose M, Sacma M, Jablanovic J, Knudson L, Nattamai KJ, Marka G, Vollmer A, Soller K, Sakk V, Cabezas‐Wallscheid N, Zheng Y, Mulaw MA, Glauche I, Geiger H. Aging alters the epigenetic asymmetry of HSC division. PLoS Biol 16: e2003389, 2018.
 168.Florian MC, Nattamai KJ, Dörr K, Marka G, Uberle B, Vas V, Eckl C, Andrä I, Schiemann M, Oostendorp RA, Scharffetter‐Kochanek K, Kestler HA, Zheng Y, Geiger H. A canonical to non‐canonical Wnt signalling switch in haematopoietic stem‐cell ageing. Nature 503: 392‐396, 2013.
 169.Fontana L, Addante F, Copetti M, Paroni G, Fontana A, Sancarlo D, Pellegrini F, Ferrucci L, Pilotto A. Identification of a metabolic signature for multidimensional impairment and mortality risk in hospitalized older patients. Aging Cell 12: 459‐466, 2013.
 170.Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, Cava E, Spelta F, Tosti V, Syed FA, Baar EL, Veronese N, Cottrell SE, Fenske RJ, Bertozzi B, Brar HK, Pietka T, Bullock AD, Figenshau RS, Andriole GL, Merrins MJ, Alexander CM, Kimple ME, Lamming DW. Decreased consumption of branched‐chain amino acids improves metabolic health. Cell Rep 16: 520‐530, 2016.
 171.Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120: 2355‐2369, 2010.
 172.Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine‐Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix‐Chornet M, Sanchez‐Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102: 10604‐10609, 2005.
 173.Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age‐associated diseases. J Gerontol A Biol Sci Med Sci 69 Suppl 1: S4‐S9, 2014.
 174.Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: A new immune‐metabolic viewpoint for age‐related diseases. Nat Rev Endocrinol 14: 576‐590, 2018.
 175.Frederick DW, Loro E, Liu L, Davila A, Chellappa K, Silverman IM, Quinn WJ, Gosai SJ, Tichy ED, Davis JG, Mourkioti F, Gregory BD, Dellinger RW, Redpath P, Migaud ME, Nakamaru‐Ogiso E, Rabinowitz JD, Khurana TS, Baur JA. Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab 24: 269‐282, 2016.
 176.Frederiksen H, Hjelmborg J, Mortensen J, McGue M, Vaupel JW, Christensen K. Age trajectories of grip strength: Cross‐sectional and longitudinal data among 8,342 Danes aged 46 to 102. Ann Epidemiol 16: 554‐562, 2006.
 177.Fried L, Cohen A, Xue Q‐L, Walston J, Bandeen‐Roche K, Varadhan R. The physical frailty syndrome as a transition from homeostatic symphony to cacophony. Nat Aging 1: 36‐46, 2021.
 178.Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: Implications for improved targeting and care. J Gerontol A Biol Sci Med Sci 59: 255‐263, 2004.
 179.Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56: M146‐M156, 2001.
 180.Fries E, Dettenborn L, Kirschbaum C. The cortisol awakening response (CAR): Facts and future directions. Int J Psychophysiol 72: 67‐73, 2009.
 181.Frisoli A, Chaves PH, Ingham SJ, Fried LP. Severe osteopenia and osteoporosis, sarcopenia, and frailty status in community‐dwelling older women: Results from the Women's Health and Aging Study (WHAS) II. Bone 48: 952‐957, 2011.
 182.Fujii N, Jessen N, Goodyear LJ. AMP‐activated protein kinase and the regulation of glucose transport. Am J Physiol Endocrinol Metab 291: E867‐E877, 2006.
 183.Fujita T, Yamashita D, Uehara N, Inokuchi G, Hasegawa S, Otsuki N, Nibu K. A high‐fat diet delays age‐related hearing loss progression in C57BL/6J mice. PLoS One 10: e0117547, 2015.
 184.Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, Miyazaki T, Ogura C, Okazaki Y, Jinno Y. Age related changes in 5‐methylcytosine content in human peripheral leukocytes and placentas: An HPLC‐based study. Ann Hum Genet 68: 196‐204, 2004.
 185.Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O'Neill HM, Ford RJ, Palanivel R, O'Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JR, van Denderen BJ, Kemp BE, Steinberg GR. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin‐sensitizing effects of metformin. Nat Med 19: 1649‐1654, 2013.
 186.Furman D, Campisi J, Verdin E, Carrera‐Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM. Chronic inflammation in the etiology of disease across the life span. Nat Med 25: 1822‐1832, 2019.
 187.Gaffey AE, Bergeman CS, Clark LA, Wirth MM. Aging and the HPA axis: Stress and resilience in older adults. Neurosci Biobehav Rev 68: 928‐945, 2016.
 188.Gale CR, Baylis D, Cooper C, Sayer AA. Inflammatory markers and incident frailty in men and women: The English Longitudinal Study of Ageing. Age (Dordr) 35: 2493‐2501, 2013.
 189.Gale CR, Cooper C, Sayer AA. Framingham cardiovascular disease risk scores and incident frailty: The English Longitudinal Study of Ageing. Age (Dordr) 36: 9692, 2014.
 190.Gale CR, Cooper C, Sayer AA. Prevalence of frailty and disability: Findings from the English Longitudinal Study of Ageing. Age Ageing 44: 162‐165, 2015.
 191.Gale CR, Marioni RE, Harris SE, Starr JM, Deary IJ. DNA methylation and the epigenetic clock in relation to physical frailty in older people: The Lothian Birth Cohort 1936. Clin Epigenetics 10: 101, 2018.
 192.Galipeau J, Sensébé L. Mesenchymal stromal cells: Clinical challenges and therapeutic opportunities. Cell Stem Cell 22: 824‐833, 2018.
 193.García‐Esquinas E, Graciani A, Guallar‐Castillón P, López‐García E, Rodríguez‐Mañas L, Rodríguez‐Artalejo F. Diabetes and risk of frailty and its potential mechanisms: A prospective cohort study of older adults. J Am Med Dir Assoc 16: 748‐754, 2015.
 194.Gardner MP, Lightman S, Sayer AA, Cooper C, Cooper R, Deeg D, Ebrahim S, Gallacher J, Kivimaki M, Kumari M, Kuh D, Martin RM, Peeters G, Ben‐Shlomo Y. Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages: An individual participant meta‐analysis. Psychoneuroendocrinology 38: 40‐49, 2013.
 195.Gardner MP, Lightman SL, Gallacher J, Hardy R, Kuh D, Ebrahim S, Bayer A, Ben‐Shlomo Y, team Hs. Diurnal cortisol patterns are associated with physical performance in the Caerphilly Prospective Study. Int J Epidemiol 40: 1693‐1702, 2011.
 196.Gerhart‐Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1alpha. EMBO J 26: 1913‐1923, 2007.
 197.Gharacholou SM, Roger VL, Lennon RJ, Rihal CS, Sloan JA, Spertus JA, Singh M. Comparison of frail patients versus nonfrail patients ≥65 years of age undergoing percutaneous coronary intervention. Am J Cardiol 109: 1569‐1575, 2012.
 198.Golpanian S, DiFede DL, Khan A, Schulman IH, Landin AM, Tompkins BA, Heldman AW, Miki R, Goldstein BJ, Mushtaq M, Levis‐Dusseau S, Byrnes JJ, Lowery M, Natsumeda M, Delgado C, Saltzman R, Vidro‐Casiano M, Pujol MV, Da Fonseca M, Oliva AA, Green G, Premer C, Medina A, Valasaki K, Florea V, Anderson E, El‐Khorazaty J, Mendizabal A, Goldschmidt‐Clermont PJ, Hare JM. Allogeneic human mesenchymal stem cell infusions for aging frailty. J Gerontol A Biol Sci Med Sci 72: 1505‐1512, 2017.
 199.Golpanian S, DiFede DL, Pujol MV, Lowery MH, Levis‐Dusseau S, Goldstein BJ, Schulman IH, Longsomboon B, Wolf A, Khan A, Heldman AW, Goldschmidt‐Clermont PJ, Hare JM. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty. Oncotarget 7: 11899‐11912, 2016.
 200.Golpanian S, El‐Khorazaty J, Mendizabal A, DiFede DL, Suncion VY, Karantalis V, Fishman JE, Ghersin E, Balkan W, Hare JM. Effect of aging on human mesenchymal stem cell therapy in ischemic cardiomyopathy patients. J Am Coll Cardiol 65: 125‐132, 2015.
 201.Golpanian S, Schulman IH, Ebert RF, Heldman AW, DiFede DL, Yang PC, Wu JC, Bolli R, Perin EC, Moyé L, Simari RD, Wolf A, Hare JM. Concise review: Review and perspective of cell dosage and routes of administration from preclinical and clinical studies of stem cell therapy for heart disease. Stem Cells Transl Med 5: 186‐191, 2016.
 202.Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the damaged heart: Mesenchymal stem cells, cell‐based therapy, and engineered heart tissue. Physiol Rev 96: 1127‐1168, 2016.
 203.Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear‐mitochondrial communication during aging. Cell 155: 1624‐1638, 2013.
 204.Gomez‐Cabrera MC, Garcia‐Valles R, Rodriguez‐Mañas L, Garcia‐Garcia FJ, Olaso‐Gonzalez G, Salvador‐Pascual A, Tarazona‐Santabalbina FJ, Viña J. A new frailty score for experimental animals based on the clinical phenotype: Inactivity as a model of frailty. J Gerontol A Biol Sci Med Sci 72: 885‐891, 2017.
 205.Gonzalez‐Freire M, Scalzo P, D'Agostino J, Moore ZA, Diaz‐Ruiz A, Fabbri E, Zane A, Chen B, Becker KG, Lehrmann E, Zukley L, Chia CW, Tanaka T, Coen PM, Bernier M, de Cabo R, Ferrucci L. Skeletal muscle ex vivo mitochondrial respiration parallels decline in vivo oxidative capacity, cardiorespiratory fitness, and muscle strength: The Baltimore Longitudinal Study of Aging. Aging Cell 17: e12725, 2018.
 206.Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV, Simonsick EM, Tylavsky FA, Visser M, Newman AB. The loss of skeletal muscle strength, mass, and quality in older adults: The Health, Aging and Body Composition Study. J Gerontol A Biol Sci Med Sci 61: 1059‐1064, 2006.
 207.Gorissen SHM, Witard OC. Characterising the muscle anabolic potential of dairy, meat and plant‐based protein sources in older adults. Proc Nutr Soc 77: 20‐31, 2018.
 208.Graber TG, Fandrey KR, Thompson LV. Novel individualized power training protocol preserves physical function in adult and older mice. Geroscience 41: 165‐183, 2019.
 209.Graber TG, Ferguson‐Stegall L, Kim JH, Thompson LV. C57BL/6 neuromuscular healthspan scoring system. J Gerontol A Biol Sci Med Sci 68: 1326‐1336, 2013.
 210.Graber TG, Ferguson‐Stegall L, Liu H, Thompson LV. Voluntary aerobic exercise reverses frailty in old mice. J Gerontol A Biol Sci Med Sci 70: 1045‐1058, 2015.
 211.Graber TG, Kim JH, Grange RW, McLoon LK, Thompson LV. C57BL/6 life span study: Age‐related declines in muscle power production and contractile velocity. Age (Dordr) 37: 9773, 2015.
 212.Graber TG, Maroto R, Fry CS, Brightwell CR, Rasmussen BB. Measuring exercise capacity and physical function in adult and older mice. J Gerontol A Biol Sci Med Sci 76: 819‐824, 2021.
 213.Graciani A, García‐Esquinas E, López‐García E, Banegas JR, Rodríguez‐Artalejo F. Ideal cardiovascular health and risk of frailty in older adults. Circ Cardiovasc Qual Outcomes 9: 239‐245, 2016.
 214.Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy‐inflammation‐cell death axis in organismal aging. Science 333: 1109‐1112, 2011.
 215.Gross AL, Xue QL, Bandeen‐Roche K, Fried LP, Varadhan R, McAdams‐DeMarco MA, Walston J, Carlson MC. Declines and impairment in executive function predict onset of physical frailty. J Gerontol A Biol Sci Med Sci 71: 1624‐1630, 2016.
 216.Hadley EC, Kuchel GA, Newman AB. Report: NIA Workshop on measures of physiologic resiliencies in human aging. J Gerontol A Biol Sci Med Sci 72: 980‐990, 2017.
 217.Hamrick MW, Herberg S, Arounleut P, He HZ, Shiver A, Qi RQ, Zhou L, Isales CM, Mi QS. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice. Biochem Biophys Res Commun 400: 379‐383, 2010.
 218.Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 100: 57‐70, 2000.
 219.Hanlon P, Nicholl BI, Jani BD, Lee D, McQueenie R, Mair FS. Frailty and pre‐frailty in middle‐aged and older adults and its association with multimorbidity and mortality: A prospective analysis of 493,737 UK Biobank participants. Lancet Public Health 3: e323‐e332, 2018.
 220.Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, Klotzle B, Bibikova M, Fan JB, Gao Y, Deconde R, Chen M, Rajapakse I, Friend S, Ideker T, Zhang K. Genome‐wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49: 359‐367, 2013.
 221.Hao Q, Song X, Yang M, Dong B, Rockwood K. Understanding risk in the oldest old: Frailty and the metabolic syndrome in a Chinese community sample aged 90+ years. J Nutr Health Aging 20: 82‐88, 2016.
 222.Hardman SE, Hall DE, Cabrera AJ, Hancock CR, Thomson DM. The effects of age and muscle contraction on AMPK activity and heterotrimer composition. Exp Gerontol 55: 120‐128, 2014.
 223.Hare JM, DiFede DL, Rieger AC, Florea V, Landin AM, El‐Khorazaty J, Khan A, Mushtaq M, Lowery MH, Byrnes JJ, Hendel RC, Cohen MG, Alfonso CE, Valasaki K, Pujol MV, Golpanian S, Ghersin E, Fishman JE, Pattany P, Gomes SA, Delgado C, Miki R, Abuzeid F, Vidro‐Casiano M, Premer C, Medina A, Porras V, Hatzistergos KE, Anderson E, Mendizabal A, Mitrani R, Heldman AW. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON‐DCM Trial. J Am Coll Cardiol 69: 526‐537, 2017.
 224.Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis‐Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW, George R, Lardo A. Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: The POSEIDON randomized trial. JAMA 308: 2369‐2379, 2012.
 225.Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB, Reisman MA, Schaer GL, Sherman W. A randomized, double‐blind, placebo‐controlled, dose‐escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 54: 2277‐2286, 2009.
 226.Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S, Simpkins JW, Smith D, Wilkinson JE, Miller RA. Acarbose, 17‐α‐estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13: 273‐282, 2014.
 227.Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460: 392‐395, 2009.
 228.Hazuda HP, Pan Q, Florez H, Luchsinger JA, Crandall JP, Venditti EM, Golden SH, Kriska AM, Bray GA. Association of intensive lifestyle and metformin interventions with frailty in the Diabetes Prevention Program Outcomes Study. J Gerontol A Biol Sci Med Sci 76: 929‐936, 2021.
 229.He YH, Lu X, Yang LQ, Xu LY, Kong QP. Association of the insulin‐like growth factor binding protein 3 (IGFBP‐3) polymorphism with longevity in Chinese nonagenarians and centenarians. Aging (Albany NY) 6: 944‐956, 2014.
 230.Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson‐Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E. Effect of 6‐month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: A randomized controlled trial. JAMA 295: 1539‐1548, 2006.
 231.Henderson YO, Bithi N, Link C, Yang J, Schugar R, Llarena N, Brown JM, Hine C. Late‐life intermittent fasting decreases aging‐related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner. Geroscience 43: 1527‐1554, 2021.
 232.Herzig S, Shaw RJ. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19: 121‐135, 2018.
 233.Hidayat K, Chen GC, Wang Y, Zhang Z, Dai X, Szeto IMY, Qin LQ. Effects of milk proteins supplementation in older adults undergoing resistance training: A meta‐analysis of randomized control trials. J Nutr Health Aging 22: 237‐245, 2018.
 234.Hilton TN, Tuttle LJ, Bohnert KL, Mueller MJ, Sinacore DR. Excessive adipose tissue infiltration in skeletal muscle in individuals with obesity, diabetes mellitus, and peripheral neuropathy: Association with performance and function. Phys Ther 88: 1336‐1344, 2008.
 235.Hindhede M. The effect of food restriction during war on mortality in Copenhagen. JAMA 74: 381‐382, 1920.
 236.Hirani V, Blyth F, Naganathan V, Le Couteur DG, Seibel MJ, Waite LM, Handelsman DJ, Cumming RG. Sarcopenia is associated with incident disability, institutionalization, and mortality in community‐dwelling older men: The Concord Health and Ageing in Men Project. J Am Med Dir Assoc 16: 607‐613, 2015.
 237.Ho TT, Warr MR, Adelman ER, Lansinger OM, Flach J, Verovskaya EV, Figueroa ME, Passegué E. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543: 205‐210, 2017.
 238.Holanda CM, Guerra RO, Nóbrega PV, Costa HF, Piuvezam MR, Maciel Á. Salivary cortisol and frailty syndrome in elderly residents of long‐stay institutions: A cross‐sectional study. Arch Gerontol Geriatr 54: e146‐e151, 2012.
 239.Hoogendijk EO, Afilalo J, Ensrud KE, Kowal P, Onder G, Fried LP. Frailty: Implications for clinical practice and public health. Lancet 394: 1365‐1375, 2019.
 240.Hooten N, Fitzpatrick M, Wood WH, De S, Ejiogu N, Zhang Y, Mattison JA, Becker KG, Zonderman AB, Evans MK. Age‐related changes in microRNA levels in serum. Aging (Albany NY) 5: 725‐740, 2013.
 241.Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 14: R115, 2013.
 242.Horvath S. Erratum to: DNA methylation age of human tissues and cell types. Genome Biol 16: 96, 2015.
 243.Horvath S, Raj K. DNA methylation‐based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19: 371‐384, 2018.
 244.Howard C, Ferrucci L, Sun K, Fried LP, Walston J, Varadhan R, Guralnik JM, Semba RD. Oxidative protein damage is associated with poor grip strength among older women living in the community. J Appl Physiol (1985) 103: 17‐20, 2007.
 245.Hu K, Zhou Q, Jiang Y, Shang Z, Mei F, Gao Q, Chen F, Zhao L, Jiang M, Ma B. Association between frailty and mortality, falls, and hospitalization among patients with hypertension: A systematic review and meta‐analysis. BioMed Research International 2021: 2690296, 2021.
 246.Hua J, Hoummady S, Muller C, Pouchelon JL, Blondot M, Gilbert C, Desquilbet L. Assessment of frailty in aged dogs. Am J Vet Res 77: 1357‐1365, 2016.
 247.Huang DD, Fan SD, Chen XY, Yan XL, Zhang XZ, Ma BW, Yu DY, Xiao WY, Zhuang CL, Yu Z. Nrf2 deficiency exacerbates frailty and sarcopenia by impairing skeletal muscle mitochondrial biogenesis and dynamics in an age‐dependent manner. Exp Gerontol 119: 61‐73, 2019.
 248.Hubbard RE, Lang IA, Llewellyn DJ, Rockwood K. Frailty, body mass index, and abdominal obesity in older people. J Gerontol A Biol Sci Med Sci 65: 377‐381, 2010.
 249.Hubbard RE, O'Mahony MS, Woodhouse KW. Characterising frailty in the clinical setting – a comparison of different approaches. Age Ageing 38: 115‐119, 2009.
 250.Huffman DM, Justice JN, Stout MB, Kirkland JL, Barzilai N, Austad SN. Evaluating health span in preclinical models of aging and disease: Guidelines, challenges, and opportunities for Geroscience. J Gerontol A Biol Sci Med Sci 71: 1395‐1406, 2016.
 251.Huizer‐Pajkos A, Kane AE, Howlett SE, Mach J, Mitchell SJ, de Cabo R, Le Couteur DG, Hilmer SN. Adverse geriatric outcomes secondary to polypharmacy in a mouse model: The influence of aging. J Gerontol A Biol Sci Med Sci 71: 571‐577, 2016.
 252.Ibrahim MM. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes Rev 11: 11‐18, 2010.
 253.Ilinca S, Calciolari S. The patterns of health care utilization by elderly Europeans: Frailty and its implications for health systems. Health Serv Res 50: 305‐320, 2015.
 254.Inglés M, Mas‐Bargues C, Gimeno‐Mallench L, Cruz‐Guerrero R, García‐García FJ, Gambini J, Borrás C, Rodríguez‐Mañas L, Viña J. Relation between genetic factors and frailty in older adults. J Am Med Dir Assoc 20: 1451‐1457, 2019.
 255.Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half‐life of endogenous GH in healthy men. J Clin Endocrinol Metab 73: 1081‐1088, 1991.
 256.Ishii S, Tanaka T, Akishita M, Ouchi Y, Tuji T, Iijima K. Metabolic syndrome, sarcopenia and role of sex and age: Cross‐sectional analysis of Kashiwa cohort study. PLoS One 9: e112718, 2014.
 257.Itoh K, Ye P, Matsumiya T, Tanji K, Ozaki T. Emerging functional cross‐talk between the Keap1‐Nrf2 system and mitochondria. J Clin Biochem Nutr 56: 91‐97, 2015.
 258.Iuchi Y, Roy D, Okada F, Kibe N, Tsunoda S, Suzuki S, Takahashi M, Yokoyama H, Yoshitake J, Kondo S, Fujii J. Spontaneous skin damage and delayed wound healing in SOD1‐deficient mice. Mol Cell Biochem 341: 181‐194, 2010.
 259.Jaenisch R, Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 33 Supp l: 245‐254, 2003.
 260.Jain S, Khera R, Corrales‐Medina VF, Townsend RR, Chirinos JA. Inflammation and arterial stiffness in humans. Atherosclerosis 237: 381‐390, 2014.
 261.Jakobsdottir S, van Nieuwpoort IC, van Bunderen CC, de Ruiter MB, Twisk JW, Deijen JB, Veltman DJ, Drent ML. Acute and short‐term effects of caloric restriction on metabolic profile and brain activation in obese, postmenopausal women. Int J Obes (Lond) 40: 1671‐1678, 2016.
 262.Jang YC, Liu Y, Hayworth CR, Bhattacharya A, Lustgarten MS, Muller FL, Chaudhuri A, Qi W, Li Y, Huang JY, Verdin E, Richardson A, Van Remmen H. Dietary restriction attenuates age‐associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD. Aging Cell 11: 770‐782, 2012.
 263.Jansen HJ, Moghtadaei M, Mackasey M, Rafferty SA, Bogachev O, Sapp JL, Howlett SE, Rose RA. Atrial structure, function and arrhythmogenesis in aged and frail mice. Sci Rep 7: 44336, 2017.
 264.Jergović M, Thompson HL, Bradshaw CM, Sonar SA, Ashgar A, Mohty N, Joseph B, Fain MJ, Cleveland K, Schnellman RG, Nikolich‐Žugich J. IL‐6 can singlehandedly drive many features of frailty in mice. Geroscience 43: 539‐549, 2021.
 265.Ji C, Xia Y, Tong S, Wu Q, Zhao Y. Association of handgrip strength with the prevalence of metabolic syndrome in US adults: The National Health and Nutrition Examination Survey. Aging (Albany NY) 12: 7818‐7829, 2020.
 266.Jin X, Ren Y, Shao L, Guo Z, Wang C, He Y, Zhou L, Cong M, Ma H, Wang W, Zhou C, Feng Y, Ba Y, Gao J, Lu M, Zhang M, Gu X, Song C, Xu H, Shi H. Prevalence of frailty and prediction of mortality in Chinese cancer patients using a frailty index‐based clinical algorithm—A multicentre study. Cancer Med 10: 6207‐6217, 2021.
 267.Johar H, Emeny RT, Bidlingmaier M, Reincke M, Thorand B, Peters A, Heier M, Ladwig KH. Blunted diurnal cortisol pattern is associated with frailty: A cross‐sectional study of 745 participants aged 65 to 90 years. J Clin Endocrinol Metab 99: E464‐E468, 2014.
 268.Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: Beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol 17: 451‐459, 2016.
 269.Johnson ML, Distelmaier K, Lanza IR, Irving BA, Robinson MM, Konopka AR, Shulman GI, Nair KS. Mechanism by which caloric restriction improves insulin sensitivity in sedentary obese adults. Diabetes 65: 74‐84, 2016.
 270.Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age‐related disease. Nature 493: 338‐345, 2013.
 271.Johnson TE. Caenorhabditis elegans 2007: The premier model for the study of aging. Exp Gerontol 43: 1‐4, 2008.
 272.Johnson TE. 25 years after age‐1: Genes, interventions and the revolution in aging research. Exp Gerontol 48: 640‐643, 2013.
 273.Johnson TE. Cell biology. Rapid aging rescue? Science 340: 1299‐1300, 2013.
 274.Johnston HE, Samant RS. Alternative systems for misfolded protein clearance: Life beyond the proteasome. FEBS J 288: 4464‐4448, 2020.
 275.Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LM, Aranda JM, Sandesara BD, Pahor M, Manini TM, Marzetti E, Leeuwenburgh C. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high‐ and low‐functioning elderly individuals. Aging Cell 11: 801‐809, 2012.
 276.Joseph GA, Wang SX, Jacobs CE, Zhou W, Kimble GC, Tse HW, Eash JK, Shavlakadze T, Glass DJ. Partial inhibition of mTORC1 in aged rats counteracts the decline in muscle mass and reverses molecular signaling associated with sarcopenia. Mol Cell Biol 39: e00141‐19, 2019.
 277.Junior G, Perez D, Tonet‐Furioso A, Gomes L, Vilaça K, Alves V, Moraes C, Nóbrega O. Circulating interleukin‐6 (but not other immune mediators) associates with criteria for Fried's Frailty among very old adults. J Aging Res 2020: 6831791, 2020.
 278.Junius‐Walker U, Onder G, Soleymani D, Wiese B, Albaina O, Bernabei R, Marzetti E. The essence of frailty: A systematic review and qualitative synthesis on frailty concepts and definitions. Eur J Intern Med 56: 3‐10, 2018.
 279.Jurk D, Wilson C, Passos JF, Oakley F, Correia‐Melo C, Greaves L, Saretzki G, Fox C, Lawless C, Anderson R, Hewitt G, Pender SL, Fullard N, Nelson G, Mann J, van de Sluis B, Mann DA, von Zglinicki T. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun 2: 4172, 2014.
 280.Justice JN, Carter CS, Beck HJ, Gioscia‐Ryan RA, McQueen M, Enoka RM, Seals DR. Battery of behavioral tests in mice that models age‐associated changes in human motor function. Age (Dordr) 36: 583‐592, 2014.
 281.Justice JN, Ferrucci L, Newman AB, Aroda VR, Bahnson JL, Divers J, Espeland MA, Marcovina S, Pollak MN, Kritchevsky SB, Barzilai N, Kuchel GA. A framework for selection of blood‐based biomarkers for Geroscience‐guided clinical trials: Report from the TAME Biomarkers Workgroup. Geroscience 40: 419‐436, 2018.
 282.Justice JN, Gregory H, Tchkonia T, LeBrasseur NK, Kirkland JL, Kritchevsky SB, Nicklas BJ. Cellular senescence biomarker p16INK4a+ cell burden in thigh adipose is associated with poor physical function in older women. J Gerontol A Biol Sci Med Sci 73: 939‐945, 2018.
 283.Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first‐in‐human, open‐label, pilot study. EBioMedicine 40: 554‐563, 2019.
 284.Kalyani RR, Corriere M, Ferrucci L. Age‐related and disease‐related muscle loss: The effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol 2: 819‐829, 2014.
 285.Kalyani RR, Tian J, Xue QL, Walston J, Cappola AR, Fried LP, Brancati FL, Blaum CS. Hyperglycemia and incidence of frailty and lower extremity mobility limitations in older women. J Am Geriatr Soc 60: 1701‐1707, 2012.
 286.Kalyani RR, Varadhan R, Weiss CO, Fried LP, Cappola AR. Frailty status and altered dynamics of circulating energy metabolism hormones after oral glucose in older women. J Nutr Health Aging 16: 679‐686, 2012.
 287.Kalyani RR, Varadhan R, Weiss CO, Fried LP, Cappola AR. Frailty status and altered glucose‐insulin dynamics. J Gerontol A Biol Sci Med Sci 67: 1300‐1306, 2012.
 288.Kameda M, Teruya T, Yanagida M, Kondoh H. Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility. Proc Natl Acad Sci U S A 117: 9483‐9489, 2020.
 289.Kane AE, Gregson E, Theou O, Rockwood K, Howlett SE. The association between frailty, the metabolic syndrome, and mortality over the lifespan. Geroscience 39: 221‐229, 2017.
 290.Kane AE, Hilmer SN, Boyer D, Gavin K, Nines D, Howlett SE, de Cabo R, Mitchell SJ. Impact of longevity interventions on a validated mouse clinical frailty index. J Gerontol A Biol Sci Med Sci 71: 333‐339, 2016.
 291.Kane AE, Hilmer SN, Huizer‐Pajkos A, Mach J, Nines D, Boyer D, Gavin K, Mitchell SJ, de Cabo R. Factors that impact on interrater reliability of the mouse clinical frailty index. J Gerontol A Biol Sci Med Sci 70: 694‐695, 2015.
 292.Kane AE, Huizer‐Pajkos A, Mach J, Mitchell SJ, de Cabo R, Le Couteur DG, Howlett SE, Hilmer SN. A comparison of two mouse frailty assessment tools. J Gerontol A Biol Sci Med Sci 72: 904‐909, 2017.
 293.Kane AE, Keller KM, Heinze‐Milne S, Grandy SA, Howlett SE. A murine frailty index based on clinical and laboratory measurements: Links between frailty and pro‐inflammatory cytokines differ in a sex‐specific manner. J Gerontol A Biol Sci Med Sci 74: 275‐282, 2019.
 294.Kane AE, Mitchell SJ, Mach J, Huizer‐Pajkos A, McKenzie C, Jones B, Cogger V, Le Couteur DG, de Cabo R, Hilmer SN. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type. Exp Gerontol 73: 95‐106, 2016.
 295.Kane AE, Shin S, Wong AA, Fertan E, Faustova NS, Howlett SE, Brown RE. Sex differences in healthspan predict lifespan in the 3xTg‐AD mouse model of Alzheimer's Disease. Front Aging Neurosci 10: 172, 2018.
 296.Karve TM, Cheema AK. Small changes huge impact: The role of protein posttranslational modifications in cellular homeostasis and disease. J Amino Acids 2011: 207691, 2011.
 297.Keating A. Mesenchymal stromal cells: New directions. Cell Stem Cell 10: 709‐716, 2012.
 298.Keithley EM, Canto C, Zheng QY, Wang X, Fischel‐Ghodsian N, Johnson KR. Cu/Zn superoxide dismutase and age‐related hearing loss. Hear Res 209: 76‐85, 2005.
 299.Keller K, Kane A, Heinze‐Milne S, Grandy SA, Howlett SE. Chronic treatment with the ACE inhibitor enalapril attenuates the development of frailty and differentially modifies pro‐and anti‐inflammatory cytokines in aging male and female C57BL/6 mice. J Gerontol A Biol Sci Med Sci 74: 1149‐1157, 2018.
 300.Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE, Rando TA, Richardson A, Schadt EE, Wyss‐Coray T, Sierra F. Geroscience: Linking aging to chronic disease. Cell 159: 709‐713, 2014.
 301.Khong SML, Lee M, Kosaric N, Khong DM, Dong Y, Hopfner U, Aitzetmüller MM, Duscher D, Schäfer R, Gurtner GC. Single‐cell transcriptomics of human mesenchymal stem cells reveal age‐related cellular subpopulation depletion and impaired regenerative function. Stem Cells 37: 240‐246, 2019.
 302.Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol 16: 263‐275, 2020.
 303.Kim JY, Park YK, Lee KP, Lee SM, Kang TW, Kim HJ, Dho SH, Kim SY, Kwon KS. Genome‐wide profiling of the microRNA‐mRNA regulatory network in skeletal muscle with aging. Aging (Albany NY) 6: 524‐544, 2014.
 304.Kim S, Myers L, Wyckoff J, Cherry KE, Jazwinski SM. The frailty index outperforms DNA methylation age and its derivatives as an indicator of biological age. Geroscience 39: 83‐92, 2017.
 305.Kirkland JL, Stout MB, Sierra F. Resilience in aging mice. J Gerontol A Biol Sci Med Sci 71: 1407‐1414, 2016.
 306.Kizilay Mancini O, Shum‐Tim D, Stochaj U, Correa JA, Colmegna I. Age, atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell‐mediated T‐cell suppression. Stem Cell Res Ther 6: 140, 2015.
 307.Ko F, Abadir P, Marx R, Westbrook R, Cooke C, Yang H, Walston J. Impaired mitochondrial degradation by autophagy in the skeletal muscle of the aged female interleukin 10 null mouse. Exp Gerontol 73: 23‐27, 2016.
 308.Ko F, Yu Q, Xue QL, Yao W, Brayton C, Yang H, Fedarko N, Walston J. Inflammation and mortality in a frail mouse model. Age (Dordr) 34: 705‐715, 2012.
 309.Kob R, Bollheimer LC, Bertsch T, Fellner C, Djukic M, Sieber CC, Fischer BE. Sarcopenic obesity: Molecular clues to a better understanding of its pathogenesis? Biogerontology 16: 15‐29, 2015.
 310.Kobayashi S, Asakura K, Suga H, Sasaki S. High protein intake is associated with low prevalence of frailty among old Japanese women: A multicenter cross‐sectional study. Nutr J 12: 164, 2013.
 311.Kohanski RA, Deeks SG, Gravekamp C, Halter JB, High K, Hurria A, Fuldner R, Green P, Huebner R, Macchiarini F, Sierra F. Reverse Geroscience: How does exposure to early diseases accelerate the age‐related decline in health? Ann N Y Acad Sci 1386: 30‐44, 2016.
 312.Kohara K. Sarcopenic obesity in aging population: Current status and future directions for research. Endocrine 45: 15‐25, 2014.
 313.Kohara K, Okada Y, Ochi M, Ohara M, Nagai T, Tabara Y, Igase M. Muscle mass decline, arterial stiffness, white matter hyperintensity, and cognitive impairment: Japan Shimanami Health Promoting Program Study. J Cachexia Sarcopenia Muscle 8: 557‐566, 2017.
 314.Koizumi Y, Hamazaki Y, Okuro M, Iritani O, Yano H, Higashikawa T, Iwai K, Morimoto S. Association between hypertension status and the screening test for frailty in elderly community‐dwelling Japanese. Hypertens Res 36: 639‐644, 2013.
 315.Kojima G, Iliffe S, Walters K. Frailty index as a predictor of mortality: A systematic review and meta‐analysis. Age Ageing 47: 193‐200, 2018.
 316.Kondoh H, Kameda M, Yanagida M. Whole blood metabolomics in aging research. Int J Mol Sci 22: 175, 2020.
 317.Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, Benavides AD, Curiel TJ, Javors MA, Musi N, Chiodo L, Koek W, Gelfond JAL, Kellogg DL. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol 105: 53‐69, 2018.
 318.Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon‐gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24: 386‐398, 2006.
 319.Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309: 481‐484, 2005.
 320.Kuo T, Harris CA, Wang JC. Metabolic functions of glucocorticoid receptor in skeletal muscle. Mol Cell Endocrinol 380: 79‐88, 2013.
 321.Kwak D, Baumann CW, Thompson LV. Identifying characteristics of frailty in female mice using a phenotype assessment tool. J Gerontol A Biol Sci Med Sci 75: 640‐646, 2020.
 322.Kwak D, Thompson LV. Frailty: Past, present, and future? Sports Med Health Sci 3: 1‐10, 2021.
 323.Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson‐Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J. MTOR regulates the pro‐tumorigenic senescence‐associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17: 1049‐1061, 2015.
 324.Lai HY, Chang HT, Lee YL, Hwang SJ. Association between inflammatory markers and frailty in institutionalized older men. Maturitas 79: 329‐333, 2014.
 325.Laksmi PW, Setiati S, Tamin TZ, Soewondo P, Rochmah W, Nafrialdi N, Prihartono J. Effect of metformin on handgrip strength, gait speed, myostatin serum level, and health‐related quality of life: A double blind randomized controlled trial among non‐diabetic pre‐frail elderly patients. Acta Med Indones 49: 118‐127, 2017.
 326.Lana A, Valdés‐Bécares A, Buño A, Rodríguez‐Artalejo F, Lopez‐Garcia E. Serum leptin concentration is associated with incident frailty in older adults. Aging Dis 8: 240‐249, 2017.
 327.Landi F, Calvani R, Cesari M, Tosato M, Martone AM, Bernabei R, Onder G, Marzetti E. Sarcopenia as the biological substrate of physical frailty. Clin Geriatr Med 31: 367‐374, 2015.
 328.Landino K, Tanaka T, Fantoni G, Candia J, Bandinelli S, Ferrucci L. Characterization of the plasma proteomic profile of frailty phenotype. Geroscience 43: 1029‐1037, 2021.
 329.Lane SW, Williams DA, Watt FM. Modulating the stem cell niche for tissue regeneration. Nat Biotechnol 32: 795‐803, 2014.
 330.Langille MG, Meehan CJ, Koenig JE, Dhanani AS, Rose RA, Howlett SE, Beiko RG. Microbial shifts in the aging mouse gut. Microbiome 2: 50, 2014.
 331.Larson‐Meyer DE, Heilbronn LK, Redman LM, Newcomer BR, Frisard MI, Anton S, Smith SR, Alfonso A, Ravussin E. Effect of calorie restriction with or without exercise on insulin sensitivity, beta‐cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 29: 1337‐1344, 2006.
 332.Layec G, Hart CR, Trinity JD, Le Fur Y, Jeong EK, Richardson RS. Skeletal muscle work efficiency with age: The role of non‐contractile processes. Clin Sci (Lond) 128: 213‐223, 2015.
 333.Le Couteur DG, Solon‐Biet SM, Cogger VC, Ribeiro R, de Cabo R, Raubenheimer D, Cooney GJ, Simpson SJ. Branched chain amino acids, aging and age‐related health. Ageing Res Rev 64: 101198, 2020.
 334.Le NP, Varadhan R, Fried LP, Cappola AR. Cortisol and dehydroepiandrosterone response to adrenocorticotropic hormone and frailty in older women. J Gerontol A Biol Sci Med Sci 76: 901‐905, 2021.
 335.LeBrasseur NK. Physical resilience: Opportunities and challenges in translation. J Gerontol A Biol Sci Med Sci 72: 978‐979, 2017.
 336.Lee CG, Boyko EJ, Strotmeyer ES, Lewis CE, Cawthon PM, Hoffman AR, Everson‐Rose SA, Barrett‐Connor E, Orwoll ES, Osteoporotic Fractures in Men Study Research Group. Association between insulin resistance and lean mass loss and fat mass gain in older men without diabetes mellitus. J Am Geriatr Soc 59: 1217‐1224, 2011.
 337.Leng S, Chaves P, Koenig K, Walston J. Serum interleukin‐6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: A pilot study. J Am Geriatr Soc 50: 1268‐1271, 2002.
 338.Leng SX, Cappola AR, Andersen RE, Blackman MR, Koenig K, Blair M, Walston JD. Serum levels of insulin‐like growth factor‐I (IGF‐I) and dehydroepiandrosterone sulfate (DHEA‐S), and their relationships with serum interleukin‐6, in the geriatric syndrome of frailty. Aging Clin Exp Res 16: 153‐157, 2004.
 339.Leng SX, Xue QL, Tian J, Huang Y, Yeh SH, Fried LP. Associations of neutrophil and monocyte counts with frailty in community‐dwelling disabled older women: Results from the Women's Health and Aging Studies I. Exp Gerontol 44: 511‐516, 2009.
 340.Leng SX, Xue QL, Tian J, Walston JD, Fried LP. Inflammation and frailty in older women. J Am Geriatr Soc 55: 864‐871, 2007.
 341.Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal‐Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP. PGC‐1alpha deficiency causes multi‐system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3: e101, 2005.
 342.Leroy L, Bayliss E, Domino M, Miller BF, Rust G, Gerteis J, Miller T. The agency for healthcare research and quality multiple chronic conditions research network: Overview of research contributions and future priorities. Med Care 52 Suppl 3: S15‐S22, 2014.
 343.Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, Whitsel EA, Wilson JG, Reiner AP, Aviv A, Lohman K, Liu Y, Ferrucci L, Horvath S. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10: 573‐591, 2018.
 344.Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara‐Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD. Low protein intake is associated with a major reduction in IGF‐1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19: 407‐417, 2014.
 345.Lewsey SC, Weiss K, Schär M, Zhang Y, Bottomley PA, Samuel TJ, Xue QL, Steinberg A, Walston JD, Gerstenblith G, Weiss RG. Exercise intolerance and rapid skeletal muscle energetic decline in human age‐associated frailty. JCI Insight 5: e141246, 2020.
 346.Liao Q, Zheng Z, Xiu S, Chan P. Waist circumference is a better predictor of risk for frailty than BMI in the community‐dwelling elderly in Beijing. Aging Clin Exp Res 30: 1319‐1325, 2018.
 347.Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care 32: 1620‐1625, 2009.
 348.Lindon JC, Nicholson JK. The emergent role of metabolic phenotyping in dynamic patient stratification. Expert Opin Drug Metab Toxicol 10: 915‐919, 2014.
 349.Liotta G, Ussai S, Illario M, O'Caoimh R, Cano A, Holland C, Roller‐Wirnsberger R, Capanna A, Grecuccio C, Ferraro M, Paradiso F, Ambrosone C, Morucci L, Scarcella P, De Luca V, Palombi L. Frailty as the future core business of public health: Report of the activities of the A3 Action Group of the European Innovation Partnership on active and healthy ageing (EIP on AHA). Int J Environ Res Public Health 15: 2843, 2018.
 350.Liu CK, Lyass A, Larson MG, Massaro JM, Wang N, D'Agostino RB, Benjamin EJ, Murabito JM. Biomarkers of oxidative stress are associated with frailty: The Framingham Offspring Study. Age (Dordr) 38: 1, 2016.
 351.Liu H, Graber TG, Ferguson‐Stegall L, Thompson LV. Clinically relevant frailty index for mice. J Gerontol A Biol Sci Med Sci 69: 1485‐1491, 2014.
 352.Liu W, Klose A, Forman S, Paris ND, Wei‐LaPierre L, Cortés‐Lopéz M, Tan A, Flaherty M, Miura P, Dirksen RT, Chakkalakal JV. Loss of adult skeletal muscle stem cells drives age‐related neuromuscular junction degeneration. Elife 6: e26464, 2017.
 353.Liu Y, Conboy MJ, Mehdipour M, Tran TP, Blotnick A, Rajan P, Santos TC, Conboy IM. Application of bio‐orthogonal proteome labeling to cell transplantation and heterochronic parabiosis. Nat Commun 8: 643, 2017.
 354.Livshits G, Malkin I, Bowyer RCE, Verdi S, Bell JT, Menni C, Williams FMK, Steves CJ. Multi‐OMICS analyses of frailty and chronic widespread musculoskeletal pain suggest involvement of shared neurological pathways. Pain 159: 2565‐2572, 2018.
 355.Locher JL, Goldsby TU, Goss AM, Kilgore ML, Gower B, Ard JD. Calorie restriction in overweight older adults: Do benefits exceed potential risks? Exp Gerontol 86: 4‐13, 2016.
 356.Loh K, Tam S, Murray‐Segal L, Huynh K, Meikle PJ, Scott JW, van Denderen B, Chen Z, Steel R, LeBlond ND, Burkovsky LA, O'Dwyer C, Nunes JRC, Steinberg GR, Fullerton MD, Galic S, Kemp BE. Inhibition of adenosine monophosphate‐activated protein kinase‐3‐hydroxy‐3‐methylglutaryl coenzyme a reductase signaling leads to hypercholesterolemia and promotes hepatic steatosis and insulin resistance. Hepatol Commun 3: 84‐98, 2019.
 357.Longo VD, Antebi A, Bartke A, Barzilai N, Brown‐Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L. Interventions to slow aging in humans: Are we ready? Aging Cell 14: 497‐510, 2015.
 358.López‐Armada MJ, Riveiro‐Naveira RR, Vaamonde‐García C, Valcárcel‐Ares MN. Mitochondrial dysfunction and the inflammatory response. Mitochondrion 13: 106‐118, 2013.
 359.López‐Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 153: 1194‐1217, 2013.
 360.Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K, Hou L, Baccarelli AA, Li Y, Stewart JD, Whitsel EA, Assimes TL, Ferrucci L, Horvath S. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY) 11: 303‐327, 2019.
 361.Lu J, Temp U, Müller‐Hartmann A, Esser J, Grönke S, Partridge L. Sestrin is a key regulator of stem cell function and lifespan in response to dietary amino acids. Nature Aging 1: 60‐72, 2021.
 362.Lukjanenko L, Jung MJ, Hegde N, Perruisseau‐Carrier C, Migliavacca E, Rozo M, Karaz S, Jacot G, Schmidt M, Li L, Metairon S, Raymond F, Lee U, Sizzano F, Wilson DH, Dumont NA, Palini A, Fässler R, Steiner P, Descombes P, Rudnicki MA, Fan CM, von Maltzahn J, Feige JN, Bentzinger CF. Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice. Nat Med 22: 897‐905, 2016.
 363.Lustgarten MS, Price LL, Chale A, Phillips EM, Fielding RA. Branched chain amino acids are associated with muscle mass in functionally limited older adults. J Gerontol A Biol Sci Med Sci 69: 717‐724, 2014.
 364.Ma L, Nidadavolu LS, Yang H, Langdon J, Westbrook R, Tsui BMW, Lee TS, Hinson J, Ling S, Marx‐Rattner R, Wu Y, Nguyen T, Tan J, Khadeer M, Moaddel R, Le A, Walston JD, Abadir PM. Targeted deletion of interleukin‐6 in a mouse model of chronic inflammation demonstrates opposing roles in aging: Benefit and harm. J Gerontol A Biol Sci Med Sci 76: 211‐215, 2021.
 365.MacDougall‐Shackleton SA, Bonier F, Romero LM, Moore IT. Glucocorticoids and “stress” are not synonymous. Integr Org Biol 1: obz017, 2019.
 366.Mach J, Gemikonakli G, Logan C, Vander Wyk B, Allore H, Ekambareshwar S, Kane AE, Howlett SE, de Cabo R, Le Couteur DG, Hilmer SN. Chronic polypharmacy with increasing drug burden index exacerbates frailty and impairs physical function, with effects attenuated by deprescribing, in aged mice. J Gerontol A Biol Sci Med Sci 76: 1010‐1018, 2021.
 367.Mahmoudi R, Jaisson S, Badr S, Jaidi Y, Bertholon LA, Novella JL, Gillery P. Post‐translational modification‐derived products are associated with frailty status in elderly subjects. Clin Chem Lab Med 57: 1153‐1161, 2019.
 368.Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med 6: 268ra179, 2014.
 369.Mannick JB, Morris M, Hockey HP, Roma G, Beibel M, Kulmatycki K, Watkins M, Shavlakadze T, Zhou W, Quinn D, Glass DJ, Klickstein LB. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med 10: eaaq1564, 2018.
 370.Marcos‐Pérez D, Sánchez‐Flores M, Maseda A, Lorenzo‐López L, Millán‐Calenti JC, Gostner JM, Fuchs D, Pásaro E, Laffon B, Valdiglesias V. Frailty in older adults is associated with plasma concentrations of inflammatory mediators but not with lymphocyte subpopulations. Front Immunol 9: 1056, 2018.
 371.Marcucci F, Romeo E, Caserta CA, Rumio C, Lefoulon F. Context‐dependent pharmacological effects of metformin on the immune system. Trends Pharmacol Sci 41: 162‐171, 2020.
 372.Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A, Meinow B, Fratiglioni L. Aging with multimorbidity: A systematic review of the literature. Ageing Res Rev 10: 430‐439, 2011.
 373.Marioni RE, Shah S, McRae AF, Ritchie SJ, Muniz‐Terrera G, Harris SE, Gibson J, Redmond P, Cox SR, Pattie A, Corley J, Taylor A, Murphy L, Starr JM, Horvath S, Visscher PM, Wray NR, Deary IJ. The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int J Epidemiol 44: 1388‐1396, 2015.
 374.Martinez de Toda I, Garrido A, Vida C, Gomez‐Cabrera MC, Viña J, De la Fuente M. Frailty quantified by the “Valencia Score” as a potential predictor of lifespan in mice. J Gerontol A Biol Sci Med Sci 73: 1323‐1329, 2018.
 375.Martin‐Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye‐Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun 4: 2192, 2013.
 376.Marzetti E, Calvani R, Tosato M, Cesari M, Di Bari M, Cherubini A, Broccatelli M, Savera G, D'Elia M, Pahor M, Bernabei R, Landi F, SPRINTT Consortium. Physical activity and exercise as countermeasures to physical frailty and sarcopenia. Aging Clin Exp Res 29: 35‐42, 2017.
 377.Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age‐associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7: e42357, 2012.
 378.Matsue Y, Kamiya K, Saito H, Saito K, Ogasahara Y, Maekawa E, Konishi M, Kitai T, Iwata K, Jujo K, Wada H, Kasai T, Nagamatsu H, Ozawa T, Izawa K, Yamamoto S, Aizawa N, Yonezawa R, Oka K, Momomura SI, Kagiyama N. Prevalence and prognostic impact of the coexistence of multiple frailty domains in elderly patients with heart failure: The FRAGILE‐HF cohort study. Eur J Heart Fail 22: 2112‐2119, 2020.
 379.Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489: 318‐321, 2012.
 380.Mazzola P, Bombelli S, Grasselli C, Bolognesi M, Antolini L, Cattoretti G, Annoni G, Perego R. Correlation between frailty and DNA damage in hematopoietic stem cells: A pilot study. Innov Aging 3: S87, 2019.
 381.Mejia‐Ramirez E, Geiger H, Florian MC. Loss of epigenetic polarity is a hallmark of hematopoietic stem cell aging. Hum Mol Genet 29: R248‐R254, 2020.
 382.Melville DM, Mohler J, Fain M, Muchna AE, Krupinski E, Sharma P, Taljanovic MS. Multi‐parametric MR imaging of quadriceps musculature in the setting of clinical frailty syndrome. Skeletal Radiol 45: 583‐589, 2016.
 383.Mercken EM, Majounie E, Ding J, Guo R, Kim J, Bernier M, Mattison J, Cookson MR, Gorospe M, de Cabo R, Abdelmohsen K. Age‐associated miRNA alterations in skeletal muscle from rhesus monkeys reversed by caloric restriction. Aging (Albany NY) 5: 692‐703, 2013.
 384.Meydani SN, Das SK, Pieper CF, Lewis MR, Klein S, Dixit VD, Gupta AK, Villareal DT, Bhapkar M, Huang M, Fuss PJ, Roberts SB, Holloszy JO, Fontana L. Long‐term moderate calorie restriction inhibits inflammation without impairing cell‐mediated immunity: A randomized controlled trial in non‐obese humans. Aging (Albany NY) 8: 1416‐1431, 2016.
 385.Migliavacca E, Tay SKH, Patel HP, Sonntag T, Civiletto G, McFarlane C, Forrester T, Barton SJ, Leow MK, Antoun E, Charpagne A, Seng Chong Y, Descombes P, Feng L, Francis‐Emmanuel P, Garratt ES, Giner MP, Green CO, Karaz S, Kothandaraman N, Marquis J, Metairon S, Moco S, Nelson G, Ngo S, Pleasants T, Raymond F, Sayer AA, Ming Sim C, Slater‐Jefferies J, Syddall HE, Fang Tan P, Titcombe P, Vaz C, Westbury LD, Wong G, Yonghui W, Cooper C, Sheppard A, Godfrey KM, Lillycrop KA, Karnani N, Feige JN. Mitochondrial oxidative capacity and NAD. Nat Commun 10: 5808, 2019.
 386.Miller MG, Thangthaeng N, Shukitt‐Hale B. A clinically relevant frailty index for aging rats. J Gerontol A Biol Sci Med Sci 72: 892‐896, 2017.
 387.Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66: 191‐201, 2011.
 388.Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13: 468‐477, 2014.
 389.Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI. Long‐term administration of nicotinamide mononucleotide mitigates age‐associated physiological decline in mice. Cell Metab 24: 795‐806, 2016.
 390.Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, Barzilai N. Low insulin‐like growth factor‐1 level predicts survival in humans with exceptional longevity. Aging Cell 13: 769‐771, 2014.
 391.Milman S, Huffman DM, Barzilai N. The somatotropic axis in human aging: Framework for the current state of knowledge and future research. Cell Metab 23: 980‐989, 2016.
 392.Mistriotis P, Bajpai VK, Wang X, Rong N, Shahini A, Asmani M, Liang MS, Wang J, Lei P, Liu S, Zhao R, Andreadis ST. NANOG reverses the myogenic differentiation potential of senescent stem cells by restoring actin filamentous organization and SRF‐dependent gene expression. Stem Cells 35: 207‐221, 2017.
 393.Mitchell SJ, Mitchell GJ, Mitchell JR. Modulation of frailty syndrome by diet: A review of evidence from mouse studies. Mech Ageing Dev 180: 82‐88, 2019.
 394.Mitnitski A, Collerton J, Martin‐Ruiz C, Jagger C, von Zglinicki T, Rockwood K, Kirkwood TB. Age‐related frailty and its association with biological markers of ageing. BMC Med 13: 161, 2015.
 395.Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure of aging. ScientificWorldJournal 1: 323‐336, 2001.
 396.Moaddel R, Fabbri E, Khadeer MA, Carlson OD, Gonzalez‐Freire M, Zhang P, Semba RD, Ferrucci L. Plasma biomarkers of poor muscle quality in older men and women from the Baltimore Longitudinal Study of Aging. J Gerontol A Biol Sci Med Sci 71: 1266‐1272, 2016.
 397.Moghtadaei M, Jansen HJ, Mackasey M, Rafferty SA, Bogachev O, Sapp JL, Howlett SE, Rose RA. The impacts of age and frailty on heart rate and sinoatrial node function. J Physiol 594: 7105‐7126, 2016.
 398.Moore DR, Churchward‐Venne TA, Witard O, Breen L, Burd NA, Tipton KD, Phillips SM. Protein ingestion to stimulate myofibrillar protein synthesis requires greater relative protein intakes in healthy older versus younger men. J Gerontol A Biol Sci Med Sci 70: 57‐62, 2015.
 399.Morley JE. Frailty: Diagnosis and management. J Nutr Health Aging 15: 667‐670, 2011.
 400.Mortensen M, Soilleux EJ, Djordjevic G, Tripp R, Lutteropp M, Sadighi‐Akha E, Stranks AJ, Glanville J, Knight S, Jacobsen SE, Kranc KR, Simon AK. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med 208: 455‐467, 2011.
 401.Most J, Tosti V, Redman LM, Fontana L. Calorie restriction in humans: An update. Ageing Res Rev 39: 36‐45, 2017.
 402.Mousa A, Savva GM, Mitnitski A, Rockwood K, Jagger C, Brayne C, Matthews FE. Is frailty a stable predictor of mortality across time? Evidence from the cognitive function and ageing studies. Age Ageing 47: 721‐727, 2018.
 403.Muller FL, Song W, Liu Y, Chaudhuri A, Pieke‐Dahl S, Strong R, Huang TT, Epstein CJ, Roberts LJ, Csete M, Faulkner JA, Van Remmen H. Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age‐dependent skeletal muscle atrophy. Free Radic Biol Med 40: 1993‐2004, 2006.
 404.Muller M, Smulders YM, de Leeuw PW, Stehouwer CD. Treatment of hypertension in the oldest old: A critical role for frailty? Hypertension 63: 433‐441, 2014.
 405.Murphy RA, Moore S, Playdon M, Kritchevsky S, Newman AB, Satterfield S, Ayonayon H, Clish C, Gerszten R, Harris TB. Metabolites associated with risk of developing mobility disability in the Health, Aging and Body Composition Study. J Gerontol A Biol Sci Med Sci 74: 73‐80, 2019.
 406.Murton AJ. Muscle protein turnover in the elderly and its potential contribution to the development of sarcopenia. Proc Nutr Soc 74: 387‐396, 2015.
 407.Myhill S, Booth NE, McLaren‐Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2: 1‐16, 2009.
 408.Nair V, Sreevalsan S, Basha R, Abdelrahim M, Abudayyeh A, Rodrigues Hoffman A, Safe S. Mechanism of metformin‐dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: Role of specificity protein (Sp) transcription factors. J Biol Chem 289: 27692‐27701, 2014.
 409.Narici MV, Maffulli N. Sarcopenia: Characteristics, mechanisms and functional significance. Br Med Bull 95: 139‐159, 2010.
 410.Newell Stamper BL, Cypser JR, Kechris K, Kitzenberg DA, Tedesco PM, Johnson TE. Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin‐like signaling pathway. Aging Cell 17: e12704, 2018.
 411.Newman AB, Gottdiener JS, Mcburnie MA, Hirsch CH, Kop WJ, Tracy R, Walston JD, Fried LP. Associations of subclinical cardiovascular disease with frailty. J Gerontol A Biol Sci Med Sci 56: M158‐M166, 2001.
 412.Newman AB, Simonsick EM, Naydeck BL, Boudreau RM, Kritchevsky SB, Nevitt MC, Pahor M, Satterfield S, Brach JS, Studenski SA, Harris TB. Association of long‐distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability. JAMA 295: 2018‐2026, 2006.
 413.Nilwik R, Snijders T, Leenders M, Groen BB, van Kranenburg J, Verdijk LB, van Loon LJ. The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. Exp Gerontol 48: 492‐498, 2013.
 414.Nóbrega‐Pereira S, Fernandez‐Marcos PJ, Brioche T, Gomez‐Cabrera MC, Salvador‐Pascual A, Flores JM, Viña J, Serrano M. G6PD protects from oxidative damage and improves healthspan in mice. Nat Commun 7: 10894, 2016.
 415.Noordam R, Jansen SW, Akintola AA, Oei NY, Maier AB, Pijl H, Slagboom PE, Westendorp RG, van der Grond J, de Craen AJ, van Heemst D. Familial longevity is marked by lower diurnal salivary cortisol levels: The Leiden Longevity Study. PLoS One 7: e31166, 2012.
 416.O'Caoimh R, Galluzzo L, Rodríguez‐Laso Á, Van der Heyden J, Ranhoff AH, Carcaillon‐Bentata L, Beltzer N, Kennelly S, Liew A. Transitions and trajectories in frailty states over time: A systematic review of the European Joint Action ADVANTAGE. Ann Ist Super Sanita 54: 246‐252, 2018.
 417.O'Caoimh R, Galluzzo L, Rodríguez‐Laso Á, Van der Heyden J, Ranhoff AH, Lamprini‐Koula M, Ciutan M, López‐Samaniego L, Carcaillon‐Bentata L, Kennelly S, Liew A. Prevalence of frailty at population level in European ADVANTAGE Joint Action Member States: A systematic review and meta‐analysis. Ann Ist Super Sanita 54: 226‐238, 2018.
 418.O'Caoimh R, Sezgin D, O'Donovan MR, Molloy DW, Clegg A, Rockwood K, Liew A. Prevalence of frailty in 62 countries across the world: A systematic review and meta‐analysis of population‐level studies. Age Ageing 50: 96‐104, 2021.
 419.Ochi M, Kohara K, Tabara Y, Kido T, Uetani E, Ochi N, Igase M, Miki T. Arterial stiffness is associated with low thigh muscle mass in middle‐aged to elderly men. Atherosclerosis 212: 327‐332, 2010.
 420.Ofori‐Asenso R, Chin KL, Mazidi M, Zomer E, Ilomaki J, Zullo AR, Gasevic D, Ademi Z, Korhonen MJ, LoGiudice D, Bell JS, Liew D. Global incidence of frailty and prefrailty among community‐dwelling older adults: A systematic review and meta‐analysis. JAMA Netw Open 2: e198398, 2019.
 421.Oh J, Lee YD, Wagers AJ. Stem cell aging: Mechanisms, regulators and therapeutic opportunities. Nat Med 20: 870‐880, 2014.
 422.O'Halloran AM, Finucane C, Savva GM, Robertson IH, Kenny RA. Sustained attention and frailty in the older adult population. J Gerontol B Psychol Sci Soc Sci 69: 147‐156, 2014.
 423.Ohlendieck K. Proteomics of skeletal muscle differentiation, neuromuscular disorders and fiber aging. Expert Rev Proteomics 7: 283‐296, 2010.
 424.Ohlendieck K. Proteomics of skeletal muscle glycolysis. Biochim Biophys Acta 1804: 2089‐2101, 2010.
 425.Okado‐Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn‐SOD in mitochondria. J Biol Chem 276: 38388‐38393, 2001.
 426.Olivieri F, Spazzafumo L, Santini G, Lazzarini R, Albertini M, Rippo M, Galeazzi R, Abbatecola A, Marcheselli F, Daniela Monti D, Rita Ostan R, Cevenini E, Antonicelli R, Franceschi C, Procopio A. Age‐related differences in the expression of circulating microRNAs: miR‐21 as a new circulating marker of inflammaging. Mech Ageing Dev 133: 675‐685, 2012.
 427.Olofsson EM, Marklund SL, Behndig A. Glucose‐induced cataract in CuZn‐SOD null lenses: An effect of nitric oxide? Free Radic Biol Med 42: 1098‐1105, 2007.
 428.Orentreich N, Matias JR, DeFelice A, Zimmerman JA. Low methionine ingestion by rats extends life span. J Nutr 123: 269‐274, 1993.
 429.Orford KW, Scadden DT. Deconstructing stem cell self‐renewal: Genetic insights into cell‐cycle regulation. Nat Rev Genet 9: 115‐128, 2008.
 430.Palikaras K, Lionaki E, Tavernarakis N. Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ 22: 1399‐1401, 2015.
 431.Panchangam C, White DA, Goudar S, Birnbaum B, Malloy‐Walton L, Gross‐Toalson J, Reid KJ, Shirali G, Parthiban A. Translation of the frailty paradigm from older adults to children with cardiac disease. Pediatr Cardiol 41: 1031‐1041, 2020.
 432.Pardon MC. Stress and ageing interactions: A paradox in the context of shared etiological and physiopathological processes. Brain Res Rev 54: 251‐273, 2007.
 433.Park Y, Choi JE, Hwang HS. Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: A randomized, double‐blind, placebo‐controlled trial. Am J Clin Nutr 108: 1026‐1033, 2018.
 434.Parks RJ, Fares E, Macdonald JK, Ernst MC, Sinal CJ, Rockwood K, Howlett SE. A procedure for creating a frailty index based on deficit accumulation in aging mice. J Gerontol A Biol Sci Med Sci 67: 217‐227, 2012.
 435.Partridge L, Deelen J, Slagboom PE. Facing up to the global challenges of ageing. Nature 561: 45‐56, 2018.
 436.Patel MS, Lee J, Baz M, Wells CE, Bloch S, Lewis A, Donaldson AV, Garfield BE, Hopkinson NS, Natanek A, Man WD, Wells DJ, Baker EH, Polkey MI, Kemp PR. Growth differentiation factor‐15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo. J Cachexia Sarcopenia Muscle 7: 436‐448, 2016.
 437.Peng PS, Kao TW, Chang PK, Chen WL, Peng PJ, Wu LW. Association between HOMA‐IR and frailty among U.S. middle‐aged and elderly population. Sci Rep 9: 4238, 2019.
 438.Pérez‐Martínez L, Romero L, Muñoz‐Galván S, Verdugo‐Sivianes EM, Rubio‐Mediavilla S, Oteo JA, Carnero A, Blanco JR. Implications of maraviroc and/or rapamycin in a mouse model of fragility. Aging (Albany NY) 12: 8565‐8582, 2020.
 439.Pérez‐Revuelta BI, Hettich MM, Ciociaro A, Rotermund C, Kahle PJ, Krauss S, Di Monte DA. Metformin lowers Ser‐129 phosphorylated α‐synuclein levels via mTOR‐dependent protein phosphatase 2A activation. Cell Death Dis 5: e1209, 2014.
 440.Pérez‐Tasigchana RF, León‐Muñoz LM, Lopez‐Garcia E, Gutierrez‐Fisac JL, Laclaustra M, Rodríguez‐Artalejo F, Guallar‐Castillón P. Metabolic syndrome and insulin resistance are associated with frailty in older adults: A prospective cohort study. Age Ageing 46: 807‐812, 2017.
 441.Perkisas S, De Cock AM, Verhoeven V, Vandewoude M. Intramuscular adipose tissue and the functional components of sarcopenia in hospitalized geriatric patients. Geriatrics (Basel) 2: 11, 2017.
 442.Perrin S. Preclinical research: Make mouse studies work. Nature 507: 423‐425, 2014.
 443.Persico I, Cesari M, Morandi A, Haas J, Mazzola P, Zambon A, Annoni G, Bellelli G. Frailty and delirium in older adults: A systematic review and meta‐analysis of the literature. J Am Geriatr Soc 66: 2022‐2030, 2018.
 444.Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. Science 300: 1140‐1142, 2003.
 445.Petr MA, Alfaras I, Krawcyzk M, Bair WN, Mitchell SJ, Morrell CH, Studenski SA, Price NL, Fishbein KW, Spencer RG, Scheibye‐Knudsen M, Lakatta EG, Ferrucci L, Aon MA, Bernier M, de Cabo R. A cross‐sectional study of functional and metabolic changes during aging through the lifespan in male mice. Elife 10: e62952, 2021.
 446.Philippou A, Halapas A, Maridaki M, Koutsilieris M. Type I insulin‐like growth factor receptor signaling in skeletal muscle regeneration and hypertrophy. J Musculoskelet Neuronal Interact 7: 208‐218, 2007.
 447.Phillips AC, Ginty AT, Hughes BM. The other side of the coin: Blunted cardiovascular and cortisol reactivity are associated with negative health outcomes. Int J Psychophysiol 90: 1‐7, 2013.
 448.Picca A, Beli R, Calvani R, Coelho‐Júnior HJ, Landi F, Bernabei R, Bucci C, Guerra F, Marzetti E. Older adults with physical frailty and sarcopenia show increased levels of circulating small extracellular vesicles with a specific mitochondrial signature. Cells 9: 973, 2020.
 449.Piggott DA, Varadhan R, Mehta SH, Brown TT, Li H, Walston JD, Leng SX, Kirk GD. Frailty, inflammation, and mortality among persons aging with HIV infection and injection drug use. J Gerontol A Biol Sci Med Sci 70: 1542‐1547, 2015.
 450.Pilotto A, Custodero C, Maggi S, Polidori MC, Veronese N, Ferrucci L. A multidimensional approach to frailty in older people. Ageing Res Rev 60: 101047, 2020.
 451.Popov LD. Mitochondrial biogenesis: An update. J Cell Mol Med 24: 4892‐4899, 2020.
 452.Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet 386: 801‐812, 2015.
 453.Prince MJ, Wu F, Guo Y, Gutierrez Robledo LM, O'Donnell M, Sullivan R, Yusuf S. The burden of disease in older people and implications for health policy and practice. Lancet 385: 549‐562, 2015.
 454.Pujos‐Guillot E, Pétéra M, Jacquemin J, Centeno D, Lyan B, Montoliu I, Madej D, Pietruszka B, Fabbri C, Santoro A, Brzozowska A, Franceschi C, Comte B. Identification of pre‐frailty sub‐phenotypes in elderly using metabolomics. Front Physiol 9: 1903, 2018.
 455.Puzianowska‐Kuźnicka M, Owczarz M, Wieczorowska‐Tobis K, Nadrowski P, Chudek J, Slusarczyk P, Skalska A, Jonas M, Franek E, Mossakowska M. Interleukin‐6 and C‐reactive protein, successful aging, and mortality: The PolSenior study. Immun Ageing 13: 21, 2016.
 456.Qu T, Yang H, Walston JD, Fedarko NS, Leng SX. Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL‐10) and its relationship with serum interleukin‐6 levels in the syndrome of frailty. Cytokine 46: 319‐324, 2009.
 457.Quéré R, Saint‐Paul L, Carmignac V, Martin RZ, Chrétien ML, Largeot A, Hammann A, Pais de Barros JP, Bastie JN, Delva L. Tif1γ regulates the TGF‐β1 receptor and promotes physiological aging of hematopoietic stem cells. Proc Natl Acad Sci U S A 111: 10592‐10597, 2014.
 458.Racette SB, Weiss EP, Villareal DT, Arif H, Steger‐May K, Schechtman KB, Fontana L, Klein S, Holloszy JO. One year of caloric restriction in humans: Feasibility and effects on body composition and abdominal adipose tissue. J Gerontol A Biol Sci Med Sci 61: 943‐950, 2006.
 459.Radloff LS. The use of the Center for Epidemiologic Studies Depression Scale in adolescents and young adults. J Youth Adolesc 20: 149‐166, 1991.
 460.Raggi C, Berardi AC. Mesenchymal stem cells, aging and regenerative medicine. Muscles Ligaments Tendons J 2: 239‐242, 2012.
 461.Ramakrishnan P, Alyousefi N, Abdul‐Rahman P, Kamaruzzaman S, Chin A, Tan M. A systematic review of studies comparing potential biochemical biomarkers of frailty with frailty assessments. Eur Geriatric Med 8: 397‐407, 2017.
 462.Ramsay SE, Arianayagam DS, Whincup PH, Lennon LT, Cryer J, Papacosta AO, Iliffe S, Wannamethee SG. Cardiovascular risk profile and frailty in a population‐based study of older British men. Heart 101: 616‐622, 2015.
 463.Rando TA, Wyss‐Coray T. Stem cells as vehicles for youthful regeneration of aged tissues. J Gerontol A Biol Sci Med Sci 69 Suppl 1: S39‐S42, 2014.
 464.Rao MS, Mattson MP. Stem cells and aging: Expanding the possibilities. Mech Ageing Dev 122: 713‐734, 2001.
 465.Rastas S, Pirttilä T, Viramo P, Verkkoniemi A, Halonen P, Juva K, Niinistö L, Mattila K, Länsimies E, Sulkava R. Association between blood pressure and survival over 9 years in a general population aged 85 and older. J Am Geriatr Soc 54: 912‐918, 2006.
 466.Rattray NJW, Trivedi DK, Xu Y, Chandola T, Johnson CH, Marshall AD, Mekli K, Rattray Z, Tampubolon G, Vanhoutte B, White IR, Wu FCW, Pendleton N, Nazroo J, Goodacre R. Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty. Nat Commun 10: 5027, 2019.
 467.Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB. A 2‐year randomized controlled trial of human caloric restriction: Feasibility and effects on predictors of health span and longevity. J Gerontol A Biol Sci Med Sci 70: 1097‐1104, 2015.
 468.Redman LM, Smith SR, Burton JH, Martin CK, Il'yasova D, Ravussin E. Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. Cell Metab 27: 805‐815.e804, 2018.
 469.Reinders I, Visser M, Schaap L. Body weight and body composition in old age and their relationship with frailty. Curr Opin Clin Nutr Metab Care 20: 11‐15, 2017.
 470.Richardson A, Fischer KE, Speakman JR, de Cabo R, Mitchell SJ, Peterson CA, Rabinovitch P, Chiao YA, Taffet G, Miller RA, Rentería RC, Bower J, Ingram DK, Ladiges WC, Ikeno Y, Sierra F, Austad SN. Measures of healthspan as indices of aging in mice – A recommendation. J Gerontol A Biol Sci Med Sci 71: 427‐430, 2016.
 471.Richardson NE, Konon EN, Schuster HS, Mitchell AT, Boyle C, Rodgers AC, Finke M, Haider LR, Yu D, Flores V, Pak HH, Ahmad S, Ahmed S, Radcliff A, Wu J, Williams EM, Abdi L, Sherman DS, Hacker T, Lamming DW. Lifelong restriction of dietary branched‐chain amino acids has sex‐specific benefits for frailty and lifespan in mice. Nat Aging 1: 73‐86, 2021.
 472.Rockwood K, Blodgett JM, Theou O, Sun MH, Feridooni HA, Mitnitski A, Rose RA, Godin J, Gregson E, Howlett SE. A frailty index based on deficit accumulation quantifies mortality risk in humans and in mice. Sci Rep 7: 43068, 2017.
 473.Rockwood K, Mitnitski A. Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med 27: 17‐26, 2011.
 474.Rockwood K, Mitnitski A, Song X, Steen B, Skoog I. Long‐term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc 54: 975‐979, 2006.
 475.Rodríguez Mañas L, García‐Sánchez I, Hendry A, Bernabei R, Roller‐Wirnsberger R, Gabrovec B, Liew A, Carriazo AM, Redon J, Galluzzo L, Viña J, Antoniadou E, Targowski T, Di Furia L, Lattanzio F, Bozdog E, Telo M. Key messages for a frailty prevention and management policy in Europe from the ADVANTAGE JOINT ACTION Consortium. J Nutr Health Aging 22: 892‐897, 2018.
 476.Rodríguez‐Fuentes D, Fernández‐Garza L, Samia‐Meza J, Barrera‐Barrera S, Caplan A, Barrera‐Saldaña H. Mesenchymal stem cells current clinical applications: A systematic review. Arch of Med Res 52: 93‐101, 2021.
 477.Rodriguez‐Mañas L, Araujo de Carvalho I, Bhasin S, Bischoff‐Ferrari HA, Cesari M, Evans W, Hare JM, Pahor M, Parini A, Rolland Y, Fielding RA, Walston J, Vellas B. ICFSR Task Force perspective on biomarkers for sarcopenia and frailty. J Frailty Aging 9: 4‐8, 2020.
 478.Romero‐Ortuno R, O'Shea D. Fitness and frailty: Opposite ends of a challenging continuum! Will the end of age discrimination make frailty assessments an imperative? Age Ageing 42: 279‐280, 2013.
 479.Rosano C, Longstreth WT, Boudreau R, Taylor CA, Du Y, Kuller LH, Newman AB. High blood pressure accelerates gait slowing in well‐functioning older adults over 18‐years of follow‐up. J Am Geriatr Soc 59: 390‐397, 2011.
 480.Rose‐John S, Winthrop K, Calabrese L. The role of IL‐6 in host defence against infections: Immunobiology and clinical implications. Nat Rev Rheumatol 13: 399‐409, 2017.
 481.Rosenberg H. Summary comments: Epidemiological and methodological problems in determining nutritional status of older persons. Am J Clin Nutr 50: 1231S‐1233S, 1989.
 482.Rosenberg IH. Sarcopenia: Origins and clinical relevance. J Nutr 127: 990S‐991S, 1997.
 483.Rusanova I, Diaz‐Casado ME, Fernández‐Ortiz M, Aranda‐Martínez P, Guerra‐Librero A, García‐García FJ, Escames G, Mañas L, Acuña‐Castroviejo D. Analysis of plasma microRNAs as predictors and biomarkers of aging and frailty in humans. Oxid Med Cell Longev 2018: 7671850, 2018.
 484.Rusanova I, Fernández‐Martínez J, Fernández‐Ortiz M, Aranda‐Martínez P, Escames G, García‐García FJ, Mañas L, Acuña‐Castroviejo D. Involvement of plasma miRNAs, muscle miRNAs and mitochondrial miRNAs in the pathophysiology of frailty. Exp Gerontol 124: 110637, 2019.
 485.Rusli F, Lute C, Boekschoten MV, van Dijk M, van Norren K, Menke AL, Müller M, Steegenga WT. Intermittent calorie restriction largely counteracts the adverse health effects of a moderate‐fat diet in aging C57BL/6J mice. Mol Nutr Food Res 61: 1600677, 2017.
 486.Ryan J, Wrigglesworth J, Loong J, Fransquet PD, Woods RL. A systematic review and meta‐analysis of environmental, lifestyle, and health factors associated with DNA methylation age. J Gerontol A Biol Sci Med Sci 75: 481‐494, 2020.
 487.Ryu D, Zhang H, Ropelle ER, Sorrentino V, Mázala DA, Mouchiroud L, Marshall PL, Campbell MD, Ali AS, Knowels GM, Bellemin S, Iyer SR, Wang X, Gariani K, Sauve AA, Cantó C, Conley KE, Walter L, Lovering RM, Chin ER, Jasmin BJ, Marcinek DJ, Menzies KJ, Auwerx J. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci Transl Med 8: 361ra139, 2016.
 488.Sabatini DM. Twenty‐five years of mTOR: Uncovering the link from nutrients to growth. Proc Natl Acad Sci U S A 114: 11818‐11825, 2017.
 489.Saisho Y. Metformin and inflammation: Its potential beyond glucose‐lowering effect. Endocr Metab Immune Disord Drug Targets 15: 196‐205, 2015.
 490.Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF‐κB signaling in the induction of senescence‐associated secretory phenotype (SASP). Cell Signal 24: 835‐845, 2012.
 491.Samson LD, Boots AMH, Verschuren WMM, Picavet HSJ, Engelfriet P, Buisman AM. Frailty is associated with elevated CRP trajectories and higher numbers of neutrophils and monocytes. Exp Gerontol 125: 110674, 2019.
 492.Santin Y, Lopez S, Ader I, Andrieu S, Blanchard N, Carrière A, Casteilla L, Cousin B, Davezac N, De Souto, Barreto P, Dray C, Fazilleau N, Gonzalez‐Dunia D, Gourdy P, Guyonnet S, Jabrane‐Ferrat N, Kunduzova O, Lezoualc'h F, Liblau R, Martinez LO, Moro C, Payoux P, Pénicaud L, Planat‐Bénard V, Rampon C, Rolland Y, Schanstra JP, Sierra F, Valet P, Varin A, Vergnolle N, Vellas B, Viña J, Guiard BP, Parini A. Towards a large‐scale assessment of the relationship between biological and chronological aging: The INSPIRE Mouse Cohort. J Frailty Aging 10: 121‐131, 2021.
 493.Santos‐Eggimann B, Cuénoud P, Spagnoli J, Junod J. Prevalence of frailty in middle‐aged and older community‐dwelling Europeans living in 10 countries. J Gerontol A Biol Sci Med Sci 64: 675‐681, 2009.
 494.Sapolsky RM. Glucocorticoids, stress, and their adverse neurological effects: Relevance to aging. Exp Gerontol 34: 721‐732, 1999.
 495.Sapolsky RM, Altmann J. Incidence of hypercortisolism and dexamethasone resistance increases with age among wild baboons. Biol Psychiatry 30: 1008‐1016, 1991.
 496.Saraiva M, O'Garra A. The regulation of IL‐10 production by immune cells. Nat Rev Immunol 10: 170‐181, 2010.
 497.Sato AY, Richardson D, Cregor M, Davis HM, Au ED, McAndrews K, Zimmers TA, Organ JM, Peacock M, Plotkin LI, Bellido T. Glucocorticoids induce bone and muscle atrophy by tissue‐specific mechanisms upstream of E3 ubiquitin ligases. Endocrinology 158: 664‐677, 2017.
 498.Saum KU, Dieffenbach AK, Jansen EH, Schottker B, Holleczek B, Hauer K, Brenner H. Association between oxidative stress and frailty in an elderly German population: Results from the ESTHER Cohort Study. Gerontology 61: 407‐415, 2015.
 499.Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 169: 361‐371, 2017.
 500.Schafer MJ, Zhang X, Kumar A, Atkinson EJ, Zhu Y, Jachim S, Mazula DL, Brown AK, Berning M, Aversa Z, Kotajarvi B, Bruce CJ, Greason KL, Suri RM, Tracy RP, Cummings SR, White TA, LeBrasseur NK. The senescence‐associated secretome as an indicator of age and medical risk. JCI Insight 5: e133668, 2020.
 501.Scheller J, Chalaris A, Schmidt‐Arras D, Rose‐John S. The pro‐ and anti‐inflammatory properties of the cytokine interleukin‐6. Biochim Biophys Acta 1813: 878‐888, 2011.
 502.Scheuren AC, D'Hulst G, Kuhn GA, Masschelein E, Wehrle E, De Bock K, Müller R. Hallmarks of frailty and osteosarcopenia in prematurely aged PolgA. J Cachexia Sarcopenia Muscle 11: 1121‐1140, 2020.
 503.Schiaffino S, Mammucari C. Regulation of skeletal muscle growth by the IGF1‐Akt/PKB pathway: Insights from genetic models. Skelet Muscle 1: 4, 2011.
 504.Schultz MB, Kane AE, Mitchell SJ, MacArthur MR, Warner E, Vogel DS, Mitchell JR, Howlett SE, Bonkowski MS, Sinclair DA. Age and life expectancy clocks based on machine learning analysis of mouse frailty. Nat Commun 11: 4618, 2020.
 505.Schultz MB, Kane AE, Mitchell SJ, MacArthur MR, Warner E, Vogel DS, Mitchell JR, Howlett SE, Bonkowski MS, Sinclair DA. Publisher Correction: Age and life expectancy clocks based on machine learning analysis of mouse frailty. Nat Commun 11: 5143, 2020.
 506.Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6: 280‐293, 2007.
 507.Scott D, Sanders KM, Aitken D, Hayes A, Ebeling PR, Jones G. Sarcopenic obesity and dynapenic obesity: 5‐year associations with falls risk in middle‐aged and older adults. Obesity (Silver Spring) 22: 1568‐1574, 2014.
 508.Seals DR, Justice JN, LaRocca TJ. Physiological Geroscience: Targeting function to increase healthspan and achieve optimal longevity. J Physiol 594: 2001‐2024, 2016.
 509.Seldeen KL, Berman RN, Pang M, Lasky G, Weiss C, MacDonald BA, Thiyagarajan R, Redae Y, Troen BR. Vitamin D insufficiency reduces grip strength, grip endurance and increases frailty in aged C57Bl/6J mice. Nutrients 12: 3005, 2020.
 510.Seldeen KL, Lasky G, Leiker MM, Pang M, Personius KE, Troen BR. High intensity interval training improves physical performance and frailty in aged mice. J Gerontol A Biol Sci Med Sci 73: 429‐437, 2018.
 511.Seldeen KL, Redae YZ, Thiyagarajan R, Berman RN, Leiker MM, Troen BR. High intensity interval training improves physical performance in aged female mice: A comparison of mouse frailty assessment tools. Mech Ageing Dev 180: 49‐62, 2019.
 512.Seldeen KL, Redae YZ, Thiyagarajan R, Berman RN, Leiker MM, Troen BR. Short session high intensity interval training and treadmill assessment in aged mice. J Vis Exp, 2019. DOI: 10.3791/59138.
 513.Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al‐Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326: 140‐144, 2009.
 514.Semba RD, Gonzalez‐Freire M, Tanaka T, Biancotto A, Zhang P, Shardell M, Moaddel R, Ferrucci L. Elevated plasma growth and differentiation factor 15 is associated with slower gait speed and lower physical performance in healthy community‐dwelling adults. J Gerontol A Biol Sci Med Sci 75: 175‐180, 2020.
 515.Sendama W. The effect of ageing on the resolution of inflammation. Ageing Res Rev 57: 101000, 2020.
 516.Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Wiley CD, Gan G, Kim DE, Kasler HG, Kuehnemann C, Kaplowitz B, Bhaumik D, Riley RR, Kennedy BK, Lithgow GJ. Alpha‐ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab 32: 447‐456.e446, 2020.
 517.Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: Is hyperinsulinemia the cart or the horse? Diabetes Care 31 Suppl 2: S262‐S268, 2008.
 518.Sharma B, Dabur R. Role of pro‐inflammatory cytokines in regulation of skeletal muscle metabolism: A systematic review. Curr Med Chem 27: 2161‐2188, 2020.
 519.Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642‐1646, 2005.
 520.Shen J, Tsai YT, Dimarco NM, Long MA, Sun X, Tang L. Transplantation of mesenchymal stem cells from young donors delays aging in mice. Sci Rep 1: 67, 2011.
 521.Short KR, Bigelow ML, Kahl J, Singh R, Coenen‐Schimke J, Raghavakaimal S, Nair KS. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A 102: 5618‐5623, 2005.
 522.Sierra F. Moving Geroscience into uncharted waters. J Gerontol A Biol Sci Med Sci 71: 1385‐1387, 2016.
 523.Sierra F. The emergence of Geroscience as an interdisciplinary approach to the enhancement of health span and life span. Cold Spring Harb Perspect Med 6: a025163, 2016.
 524.Sierra F, Kohanski R. Geroscience and the trans‐NIH Geroscience Interest Group, GSIG. Geroscience 39: 1‐5, 2017.
 525.Sierra MI, Fernández AF, Fraga MF. Epigenetics of aging. Curr Genomics 16: 435‐440, 2015.
 526.Sikka G, Miller KL, Steppan J, Pandey D, Jung SM, Fraser CD, Ellis C, Ross D, Vandegaer K, Bedja D, Gabrielson K, Walston JD, Berkowitz DE, Barouch LA. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age. Exp Gerontol 48: 128‐135, 2013.
 527.Simonsick EM, Glynn NW, Jerome GJ, Shardell M, Schrack JA, Ferrucci L. Fatigued, but not frail: Perceived fatigability as a marker of impending decline in mobility‐intact older adults. J Am Geriatr Soc 64: 1287‐1292, 2016.
 528.Simpkin AJ, Cooper R, Howe LD, Relton CL, Davey Smith G, Teschendorff A, Widschwendter M, Wong A, Kuh D, Hardy R. Are objective measures of physical capability related to accelerated epigenetic age? Findings from a British birth cohort. BMJ Open 7: e016708, 2017.
 529.Sinclair DA, Dunning T, Rodriguez‐Mañas L. Diabetes in older people: New insights and remaining challenges. Lancet Diabetes Endocrinol 3: 275‐285, 2015.
 530.Singh M, Jensen MD, Lerman A, Kushwaha S, Rihal CS, Gersh BJ, Behfar A, Tchkonia T, Thomas RJ, Lennon RJ, Keenan LR, Moore AG, Kirkland JL. Effect of low‐dose rapamycin on senescence markers and physical functioning in older adults with coronary artery disease: Results of a pilot study. J Frailty Aging 5: 204‐207, 2016.
 531.Siriwardhana DD, Hardoon S, Rait G, Weerasinghe MC, Walters KR. Prevalence of frailty and prefrailty among community‐dwelling older adults in low‐income and middle‐income countries: A systematic review and meta‐analysis. BMJ Open 8: e018195, 2018.
 532.Skorupa DA, Dervisefendic A, Zwiener J, Pletcher SD. Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster. Aging Cell 7: 478‐490, 2008.
 533.Solmi M, Veronese N, Luchini C, Manzato E, Sergi G, Favaro A, Santonastaso P, Correll CU. Oxidative stress and antioxidant levels in patients with anorexia nervosa after oral re‐alimentation: A systematic review and exploratory meta‐analysis. Eur Eat Disord Rev 24: 101‐105, 2016.
 534.Solmi M, Veronese N, Manzato E, Sergi G, Favaro A, Santonastaso P, Correll CU. Oxidative stress and antioxidant levels in patients with anorexia nervosa: A systematic review and exploratory meta‐analysis. Int J Eat Disord 48: 826‐841, 2015.
 535.Solon‐Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC, Warren A, Huang X, Pichaud N, Melvin RG, Gokarn R, Khalil M, Turner N, Cooney GJ, Sinclair DA, Raubenheimer D, Le Couteur DG, Simpson SJ. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum‐fed mice. Cell Metab 19: 418‐430, 2014.
 536.Song X, Mitnitski A, Rockwood K. Prevalence and 10‐year outcomes of frailty in older adults in relation to deficit accumulation. J Am Geriatr Soc 58: 681‐687, 2010.
 537.Sonowal R, Swimm A, Sahoo A, Luo L, Matsunaga Y, Wu Z, Bhingarde JA, Ejzak EA, Ranawade A, Qadota H, Powell DN, Capaldo CT, Flacker JM, Jones RM, Benian GM, Kalman D. Indoles from commensal bacteria extend healthspan. Proc Natl Acad Sci U S A 114: E7506‐E7515, 2017.
 538.Sousa‐Victor P, Gutarra S, García‐Prat L, Rodriguez‐Ubreva J, Ortet L, Ruiz‐Bonilla V, Jardí M, Ballestar E, González S, Serrano AL, Perdiguero E, Muñoz‐Cánoves P. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506: 316‐321, 2014.
 539.Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M, Peluso R, Sergi G, Isik AT, Manzato E, Maggi S, Maggio M, Prina AM, Cosco TD, Wu YT, Veronese N. Inflammation and frailty in the elderly: A systematic review and meta‐analysis. Ageing Res Rev 31: 1‐8, 2016.
 540.Spira D, Buchmann N, Nikolov J, Demuth I, Steinhagen‐Thiessen E, Eckardt R, Norman K. Association of low lean mass with frailty and physical performance: A comparison between two operational definitions of sarcopenia‐data from the Berlin Aging Study II (BASE‐II). J Gerontol A Biol Sci Med Sci 70: 779‐784, 2015.
 541.Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: An update. Cell Transplant 25: 829‐848, 2016.
 542.Steffl M, Bohannon RW, Sontakova L, Tufano JJ, Shiells K, Holmerova I. Relationship between sarcopenia and physical activity in older people: A systematic review and meta‐analysis. Clin Interv Aging 12: 835‐845, 2017.
 543.Stenholm S, Strandberg TE, Pitkälä K, Sainio P, Heliövaara M, Koskinen S. Midlife obesity and risk of frailty in old age during a 22‐year follow‐up in men and women: The Mini‐Finland Follow‐up Survey. J Gerontol A Biol Sci Med Sci 69: 73‐78, 2014.
 544.Stolzing A, Jones E, McGonagle D, Scutt A. Age‐related changes in human bone marrow‐derived mesenchymal stem cells: Consequences for cell therapies. Mech Ageing Dev 129: 163‐173, 2008.
 545.Stout MB, Steyn FJ, Jurczak MJ, Camporez JG, Zhu Y, Hawse JR, Jurk D, Palmer AK, Xu M, Pirtskhalava T, Evans GL, de Souza Santos R, Frank AP, White TA, Monroe DG, Singh RJ, Casaclang‐Verzosa G, Miller JD, Clegg DJ, LeBrasseur NK, von Zglinicki T, Shulman GI, Tchkonia T, Kirkland JL. 17alpha‐estradiol alleviates age‐related metabolic and inflammatory dysfunction in male mice without inducing feminization. J Gerontol A Biol Sci Med Sci 72: 3‐15, 2017.
 546.Strandberg TE, Pitkälä KH. Frailty in elderly people. Lancet 369: 1328‐1329, 2007.
 547.Strandberg TE, Sirola J, Pitkälä KH, Tilvis RS, Strandberg AY, Stenholm S. Association of midlife obesity and cardiovascular risk with old age frailty: A 26‐year follow‐up of initially healthy men. Int J Obes (Lond) 36: 1153‐1157, 2012.
 548.Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P. Functionally significant insulin‐like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 105: 3438‐3442, 2008.
 549.Sukoff Rizzo SJ, Anderson LC, Green TL, McGarr T, Wells G, Winter SS. Assessing healthspan and lifespan measures in aging mice: Optimization of testing protocols, replicability, and rater reliability. Curr Protoc Mouse Biol 8: e45, 2018.
 550.Sumantri S, Setiati S, Purnamasari D, Dewiasty E. Relationship between metformin and frailty syndrome in elderly people with Type 2 diabetes. Acta Med Indonesia 46: 183‐188, 2014.
 551.Sun B, Jeong YH, Jung JW, Seo K, Lee YS, Kang KS. Regulation of human umbilical cord blood‐derived multi‐potent stem cells by autogenic osteoclast‐based niche‐like structure. Biochem Biophys Res Commun 357: 92‐98, 2007.
 552.Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell 61: 654‐666, 2016.
 553.Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4: 141‐194, 2005.
 554.Takeda C, Angioni D, Setphan E, Macaron T, De Souto Barreto P, Sourdet S, Sierra F, Vellas B. Age‐related frailty: A clinical model for Geroscience? J Nutr Health Aging 24: 1140‐1143, 2020.
 555.Takeuchi I, Yoshimura Y, Shimazu S, Jeong S, Yamaga M, Koga H. Effects of branched‐chain amino acids and vitamin D supplementation on physical function, muscle mass and strength, and nutritional status in sarcopenic older adults undergoing hospital‐based rehabilitation: A multicenter randomized controlled trial. Geriatr Gerontol Int 19: 12‐17, 2019.
 556.Tanaka T, Narazaki M, Kishimoto T. IL‐6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6: a016295, 2014.
 557.Tang H, Inoki K, Brooks SV, Okazawa H, Lee M, Wang J, Kim M, Kennedy CL, Macpherson PCD, Ji X, Van Roekel S, Fraga DA, Wang K, Zhu J, Wang Y, Sharp ZD, Miller RA, Rando TA, Goldman D, Guan KL, Shrager JB. mTORC1 underlies age‐related muscle fiber damage and loss by inducing oxidative stress and catabolism. Aging Cell 18: e12943, 2019.
 558.Tarragó MG, Chini CCS, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN. A potent and specific CD38 inhibitor ameliorates age‐related metabolic dysfunction by reversing tissue NAD. Cell Metab 27: 1081‐1095.e1010, 2018.
 559.Tashiro J, Elliot SJ, Gerth DJ, Xia X, Pereira‐Simon S, Choi R, Catanuto P, Shahzeidi S, Toonkel RL, Shah RH, El Salem F, Glassberg MK. Therapeutic benefits of young, but not old, adipose‐derived mesenchymal stem cells in a chronic mouse model of bleomycin‐induced pulmonary fibrosis. Transl Res 166: 554‐567, 2015.
 560.Tchkonia T, Palmer A, Kirkland J. New horizons: Novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J Clin Endocrinol Metab 106: E1481‐E1487, 2021.
 561.Theou O, Stathokostas L, Roland KP, Jakobi JM, Patterson C, Vandervoort AA, Jones GR. The effectiveness of exercise interventions for the management of frailty: A systematic review. J Aging Res 2011: 569194, 2011.
 562.Tidball JG. Regulation of muscle growth and regeneration by the immune system. Nat Rev Immunol 17: 165‐178, 2017.
 563.Todorovic ST, Smiljanic KR, Ruzdijic SD, Djordjevic ANM, Kanazir SD. Effects of different dietary protocols on general activity and frailty of male wistar rats during aging. J Gerontol A Biol Sci Med Sci 73: 1036‐1044, 2018.
 564.Tompkins BA, DiFede DL, Khan A, Landin AM, Schulman IH, Pujol MV, Heldman AW, Miki R, Goldschmidt‐Clermont PJ, Goldstein BJ, Mushtaq M, Levis‐Dusseau S, Byrnes JJ, Lowery M, Natsumeda M, Delgado C, Saltzman R, Vidro‐Casiano M, Da Fonseca M, Golpanian S, Premer C, Medina A, Valasaki K, Florea V, Anderson E, El‐Khorazaty J, Mendizabal A, Green G, Oliva AA, Hare JM. Allogeneic mesenchymal stem cells ameliorate aging frailty: A phase II randomized, double‐blind, placebo‐controlled clinical trial. J Gerontol A Biol Sci Med Sci 72: 1513‐1522, 2017.
 565.Torgovnick A, Schiavi A, Maglioni S, Ventura N. Healthy aging: What can we learn from Caenorhabditis elegans? Z Gerontol Geriatr 46: 623‐628, 2013.
 566.Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo‐Kallanian S, Williams IR, Sears C, Armstrong SA, Passegué E, DePinho RA, Gilliland DG. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128: 325‐339, 2007.
 567.Troncoso R, Ibarra C, Vicencio JM, Jaimovich E, Lavandero S. New insights into IGF‐1 signaling in the heart. Trends Endocrinol Metab 25: 128‐137, 2014.
 568.Trounson A, McDonald C. Stem cell therapies in clinical trials: Progress and challenges. Cell Stem Cell 17: 11‐22, 2015.
 569.Tsai VW, Lin S, Brown DA, Salis A, Breit SN. Anorexia‐cachexia and obesity treatment may be two sides of the same coin: Role of the TGF‐b superfamily cytokine MIC‐1/GDF15. Int J Obes (Lond) 40: 193‐197, 2016.
 570.Tuttle LJ, Hastings MK, Mueller MJ. A moderate‐intensity weight‐bearing exercise program for a person with type 2 diabetes and peripheral neuropathy. Phys Ther 92: 133‐141, 2012.
 571.Tuttle LJ, Sinacore DR, Cade WT, Mueller MJ. Lower physical activity is associated with higher intermuscular adipose tissue in people with type 2 diabetes and peripheral neuropathy. Phys Ther 91: 923‐930, 2011.
 572.Valdiglesias V, Sánchez‐Flores M, Marcos‐Pérez D, Lorenzo‐López L, Maseda A, Millán‐Calenti JC, Pásaro E, Laffon B. Exploring genetic outcomes as frailty biomarkers. J Gerontol A Biol Sci Med Sci 74: 168‐175, 2019.
 573.van Abbema R, Bielderman A, De Greef M, Hobbelen H, Krijnen W, van der Schans C. Building from a conceptual model of the resilience process during ageing, towards the Groningen Aging Resilience Inventory. J Adv Nurs 71: 2208‐2219, 2015.
 574.van de Weijer T, Phielix E, Bilet L, Williams EG, Ropelle ER, Bierwagen A, Livingstone R, Nowotny P, Sparks LM, Paglialunga S, Szendroedi J, Havekes B, Moullan N, Pirinen E, Hwang JH, Schrauwen‐Hinderling VB, Hesselink MK, Auwerx J, Roden M, Schrauwen P. Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes 64: 1193‐1201, 2015.
 575.van der Spoel E, Jansen SW, Akintola AA, Ballieux BE, Cobbaert CM, Slagboom PE, Blauw GJ, Westendorp RGJ, Pijl H, Roelfsema F, van Heemst D. Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity. Aging Cell 15: 1126‐1131, 2016.
 576.van der Spoel E, Rozing MP, Houwing‐Duistermaat JJ, Slagboom PE, Beekman M, de Craen AJ, Westendorp RG, van Heemst D. Association analysis of insulin‐like growth factor‐1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study. Aging (Albany NY) 7: 956‐963, 2015.
 577.van Niekerk G, du Toit A, Loos B, Engelbrecht AM. Nutrient excess and autophagic deficiency: Explaining metabolic diseases in obesity. Metabolism 82: 14‐21, 2018.
 578.van Nieuwpoort IC, Vlot MC, Schaap LA, Lips P, Drent ML. The relationship between serum IGF‐1, handgrip strength, physical performance and falls in elderly men and women. Eur J Endocrinol 179: 73‐84, 2018.
 579.Vandamme TF. Use of rodents as models of human diseases. J Pharm Bioallied Sci 6: 2‐9, 2014.
 580.Varadhan R, Russ DW, Gabr RE, Huang J, Kalyani RR, Xue QL, Cappola AR, Bandeen‐Roche K, Fried LP. Relationship of physical frailty to phosphocreatine recovery in muscle after mild exercise stress in the oldest‐old women. J Frailty Aging 8: 162‐168, 2019.
 581.Varadhan R, Walston J, Cappola AR, Carlson MC, Wand GS, Fried LP. Higher levels and blunted diurnal variation of cortisol in frail older women. J Gerontol A Biol Sci Med Sci 63: 190‐195, 2008.
 582.Varadhan R, Yao W, Matteini A, Beamer BA, Xue QL, Yang H, Manwani B, Reiner A, Jenny N, Parekh N, Fallin MD, Newman A, Bandeen‐Roche K, Tracy R, Ferrucci L, Walston J. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all‐cause mortality in older adults. J Gerontol A Biol Sci Med Sci 69: 165‐173, 2014.
 583.Vasilaki A, Richardson A, Van Remmen H, Brooks SV, Larkin L, McArdle A, Jackson MJ. Role of nerve‐muscle interactions and reactive oxygen species in regulation of muscle proteostasis with ageing. J Physiol 595: 6409‐6415, 2017.
 584.Veeranki S, Tyagi SC. Defective homocysteine metabolism: Potential implications for skeletal muscle malfunction. Int J Mol Sci 14: 15074‐15091, 2013.
 585.Veeranki S, Winchester LJ, Tyagi SC. Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications. Biochim Biophys Acta: 732, 2015‐741, 1852.
 586.Velloso CP. Regulation of muscle mass by growth hormone and IGF‐I. Br J Pharmacol 154: 557‐568, 2008.
 587.Veronese N, Cereda E, Solmi M, Fowler SA, Manzato E, Maggi S, Manu P, Abe E, Hayashi K, Allard JP, Arendt BM, Beck A, Chan M, Audrey YJ, Lin WY, Hsu HS, Lin CC, Diekmann R, Kimyagarov S, Miller M, Cameron ID, Pitkälä KH, Lee J, Woo J, Nakamura K, Smiley D, Umpierrez G, Rondanelli M, Sund‐Levander M, Valentini L, Schindler K, Törmä J, Volpato S, Zuliani G, Wong M, Lok K, Kane JM, Sergi G, Correll CU. Inverse relationship between body mass index and mortality in older nursing home residents: A meta‐analysis of 19,538 elderly subjects. Obes Rev 16: 1001‐1015, 2015.
 588.Verovskaya EV, Dellorusso PV, Passegué E. Losing sense of self and surroundings: Hematopoietic stem cell aging and leukemic transformation. Trends Mol Med 25: 494‐515, 2019.
 589.Vetrano DL, Palmer K, Marengoni A, Marzetti E, Lattanzio F, Roller‐Wirnsberger R, Lopez Samaniego L, Rodríguez‐Mañas L, Bernabei R, Onder G. Frailty and multimorbidity: A systematic review and meta‐analysis. J Gerontol A Biol Sci Med Sci 74: 659‐666, 2019.
 590.Vetrano DL, Palmer KM, Galluzzo L, Giampaoli S, Marengoni A, Bernabei R, Onder G. Hypertension and frailty: A systematic review and meta‐analysis. BMJ Open 8: e024406, 2018.
 591.Vijg J, Suh Y. Genome instability and aging. Annu Rev Physiol 75: 645‐668, 2013.
 592.Villacampa‐Fernández P, Navarro‐Pardo E, Tarín JJ, Cano A. Frailty and multimorbidity: Two related yet different concepts. Maturitas 95: 31‐35, 2017.
 593.Viscogliosi G. The metabolic syndrome: A risk factor for the frailty syndrome? J Am Med Dir Assoc 17: 364‐366, 2016.
 594.Vizoso FJ, Eiro N, Costa L, Esparza P, Landin M, Diaz‐Rodriguez P, Schneider J, Perez‐Fernandez R. Mesenchymal stem cells in homeostasis and systemic diseases: Hypothesis, evidences, and therapeutic opportunities. Int J Mol Sci 20: 3738, 2019.
 595.Vogeli C, Shields AE, Lee TA, Gibson TB, Marder WD, Weiss KB, Blumenthal D. Multiple chronic conditions: Prevalence, health consequences, and implications for quality, care management, and costs. J Gen Intern Med 22 Suppl 3: 391‐395, 2007.
 596.Wall BT, Gorissen SH, Pennings B, Koopman R, Groen BB, Verdijk LB, van Loon LJ. Aging is accompanied by a blunted muscle protein synthetic response to protein ingestion. PLoS One 10: e0140903, 2015.
 597.Walston J, Bandeen‐Roche K, Buta B, Bergman H, Gill TM, Morley JE, Fried LP, Robinson TN, Afilalo J, Newman AB, López‐Otín C, De Cabo R, Theou O, Studenski S, Cohen HJ, Ferrucci L. Moving frailty toward clinical practice: NIA Intramural Frailty Science Symposium Summary. J Am Geriatr Soc 67: 1559‐1564, 2019.
 598.Walston J, Fedarko N, Yang H, Leng S, Beamer B, Espinoza S, Lipton A, Zheng H, Becker K. The physical and biological characterization of a frail mouse model. J Gerontol A Biol Sci Med Sci 63: 391‐398, 2008.
 599.Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, Studenski SA, Ershler WB, Harris T, Fried LP. Research agenda for frailty in older adults: Toward a better understanding of physiology and etiology: Summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 54: 991‐1001, 2006.
 600.Walston J, McBurnie MA, Newman A, Tracy RP, Kop WJ, Hirsch CH, Gottdiener J, Fried LP. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: Results from the Cardiovascular Health Study. Arch Intern Med 162: 2333‐2341, 2002.
 601.Walston JD, Bandeen‐Roche K. Frailty: A tale of two concepts. BMC Med 13: 185, 2015.
 602.Wang B, Liu Z, Chen VP, Wang L, Inman CL, Zhou Y, Guo C, Tchkonia T, Rowe DW, Kuchel GA, Robson P, Kirkland JL, Xu M. Transplanting cells from old but not young donors causes physical dysfunction in older recipients. Aging Cell 19: e13106, 2020.
 603.Wang CP, Lorenzo C, Espinoza SE. Frailty attenuates the impact of metformin on reducing mortality in older adults with type 2 diabetes. J Endocrinol Diabetes Obes 2: 1031, 2014.
 604.Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J, Passegué E. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494: 323‐327, 2013.
 605.Washburn RA, Smith KW, Jette AM, Janney CA. The physical activity scale for the elderly (PASE): Development and evaluation. J Clin Epidemiol 46: 153‐162, 1993.
 606.Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: A new trend for cell therapy. Acta Pharmacol Sin 34: 747‐754, 2013.
 607.Weidner CI, Wagner W. The epigenetic tracks of aging. Biol Chem 395: 1307‐1314, 2014.
 608.Wenz T. PGC‐1alpha activation as a therapeutic approach in mitochondrial disease. IUBMB Life 61: 1051‐1062, 2009.
 609.Westbrook RM, Yang HL, Langdon JM, Roy CN, Kim JA, Choudhury PP, Xue QL, di Francesco A, de Cabo R, Walston J. Aged interleukin‐10tm1Cgn chronically inflamed mice have substantially reduced fat mass, metabolic rate, and adipokines. PLoS One 12: e0186811, 2017.
 610.Westerblad H, Bruton JD, Katz A. Skeletal muscle: Energy metabolism, fiber types, fatigue and adaptability. Exp Cell Res 316: 3093‐3099, 2010.
 611.Whitehead JC, Hildebrand BA, Sun M, Rockwood MR, Rose RA, Rockwood K, Howlett SE. A clinical frailty index in aging mice: Comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci 69: 621‐632, 2014.
 612.Whitson HE, Cohen HJ, Schmader KE, Morey MC, Kuchel G, Colon‐Emeric CS. Physical resilience: Not simply the opposite of frailty. J Am Geriatr Soc 66: 1459‐1461, 2018.
 613.Whitson HE, Duan‐Porter W, Schmader KE, Morey MC, Cohen HJ, Colón‐Emeric CS. Physical resilience in older adults: Systematic review and development of an emerging construct. J Gerontol A Biol Sci Med Sci 71: 489‐495, 2016.
 614.Wieling W, Krediet CT, van Dijk N, Linzer M, Tschakovsky ME. Initial orthostatic hypotension: Review of a forgotten condition. Clin Sci (Lond) 112: 157‐165, 2007.
 615.Wilkinson DJ, Piasecki M, Atherton PJ. The age‐related loss of skeletal muscle mass and function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans. Ageing Res Rev 47: 123‐132, 2018.
 616.Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He Q, Curb JD, Suzuki M. Caloric restriction, the traditional Okinawan diet, and healthy aging: The diet of the world's longest‐lived people and its potential impact on morbidity and life span. Ann N Y Acad Sci 1114: 434‐455, 2007.
 617.Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 11: 228‐234, 2009.
 618.Wong SQ, Kumar AV, Mills J, Lapierre LR. Autophagy in aging and longevity. Hum Genet 139: 277‐290, 2020.
 619.Wong SQ, Kumar AV, Mills J, Lapierre LR. C. elegans to model autophagy‐related human disorders. Prog Mol Biol Transl Sci 172: 325‐373, 2020.
 620.Wong TY, Massa MS, O'Halloran AM, Kenny RA, Clarke R. Cardiovascular risk factors and frailty in a cross‐sectional study of older people: Implications for prevention. Age Ageing 47: 714‐720, 2018.
 621.Woolford SJ, Sohan O, Dennison EM, Cooper C, Patel HP. Approaches to the diagnosis and prevention of frailty. Aging Clin Exp Res 32: 1629‐1637, 2020.
 622.Workeneh B, Bajaj M. The regulation of muscle protein turnover in diabetes. Int J Biochem Cell Biol 45: 2239‐2244, 2013.
 623.World Health Organization. World Report on Ageing and Health. Geneva: World Health Organization, 2015.
 624.World Health Organization. Integrated Care for Older People: Guidelines on Community‐Level Interventions to Manage Declines in Intrinsic Capacity. Geneva: World Health Organization, Licence: CC BY‐NC‐SA 3.0 IGO, 2017.
 625.Xie WQ, Xiao WF, Tang K, Wu YX, Hu PW, Li YS, Duan Y, Lv S. Caloric restriction: Implications for sarcopenia and potential mechanisms. Aging (Albany NY) 12: 24441‐24452, 2020.
 626.Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, Onken JL, Johnson KO, Verzosa GC, Langhi LGP, Weigl M, Giorgadze N, LeBrasseur NK, Miller JD, Jurk D, Singh RJ, Allison DB, Ejima K, Hubbard GB, Ikeno Y, Cubro H, Garovic VD, Hou X, Weroha SJ, Robbins PD, Niedernhofer LJ, Khosla S, Tchkonia T, Kirkland JL. Senolytics improve physical function and increase lifespan in old age. Nat Med 24: 1246‐1256, 2018.
 627.Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, Pirtskhalava T, White TA, Johnson KO, Stout MB, Mezera V, Giorgadze N, Jensen MD, LeBrasseur NK, Kirkland JL. JAK inhibition alleviates the cellular senescence‐associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A 112: E6301‐E6310, 2015.
 628.Xue QL. The frailty syndrome: Definition and natural history. Clin Geriatr Med 27: 1‐15, 2011.
 629.Xue QL, Tian J, Walston JD, Chaves PHM, Newman AB, Bandeen‐Roche K. Discrepancy in frailty identification: Move beyond predictive validity. J Gerontol A Biol Sci Med Sci 75: 387‐393, 2020.
 630.Xue QL, Walston JD, Fried LP, Beamer BA. Prediction of risk of falling, physical disability, and frailty by rate of decline in grip strength: The Women's Health and Aging Study. Arch Intern Med 171: 1119‐1121, 2011.
 631.Yamada Y, Kemnitz JW, Weindruch R, Anderson RM, Schoeller DA, Colman RJ. Caloric restriction and healthy life span: Frail phenotype of nonhuman primates in the Wisconsin National Primate Research Center Caloric Restriction Study. J Gerontol A Biol Sci Med Sci 73: 273‐278, 2018.
 632.Yanagita I, Fujihara Y, Kitajima Y, Tajima M, Honda M, Kawajiri T, Eda T, Yonemura K, Yamaguchi N, Asakawa H, Nei Y, Kayashima Y, Yoshimoto M, Harada M, Araki Y, Yoshimoto S, Aida E, Yanase T, Nawata H, Muta K. A high serum cortisol/DHEA‐S ratio is a risk factor for sarcopenia in elderly diabetic patients. J Endocr Soc 3: 801‐813, 2019.
 633.Yao X, Hamilton RG, Weng NP, Xue QL, Bream JH, Li H, Tian J, Yeh SH, Resnick B, Xu X, Walston J, Fried LP, Leng SX. Frailty is associated with impairment of vaccine‐induced antibody response and increase in post‐vaccination influenza infection in community‐dwelling older adults. Vaccine 29: 5015‐5021, 2011.
 634.Ye X, Liao C, Liu G, Xu Y, Tan J, Song Z. Age‐related changes in the regenerative potential of adipose‐derived stem cells isolated from the prominent fat pads in human lower eyelids. PLoS One 11: e0166590, 2016.
 635.Yorke A, Kane AE, Hancock Friesen CL, Howlett SE, O'Blenes S. Development of a rat clinical frailty index. J Gerontol A Biol Sci Med Sci 72: 897‐903, 2017.
 636.Yoshida S, Yamahara K, Kume S, Koya D, Yasuda‐Yamahara M, Takeda N, Osawa N, Chin‐Kanasaki M, Adachi Y, Nagao K, Maegawa H, Araki SI. Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice. Aging Cell 17: e12796, 2018.
 637.Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet‐ and age‐induced diabetes in mice. Cell Metab 14: 528‐536, 2011.
 638.Yu R, Wong M, Chong KC, Chang B, Lum CM, Auyeung TW, Lee J, Lee R, Woo J. Trajectories of frailty among Chinese older people in Hong Kong between 2001 and 2012: An age‐period‐cohort analysis. Age Ageing 47: 254‐261, 2018.
 639.Yuan J, Liu Y, Wang J, Zhao Y, Li K, Jing Y, Zhang X, Liu Q, Geng X, Li G, Wang F. Long‐term persistent organic pollutants exposure induced telomere dysfunction and senescence‐associated secretary phenotype. J Gerontol A Biol Sci Med Sci 73: 1027‐1035, 2018.
 640.Zamboni M, Gattazzo S, Rossi AP. Myosteatosis: A relevant, yet poorly explored element of sarcopenia. Eur Geriatr Med 10: 5‐6, 2019.
 641.Zampieri M, Ciccarone F, Calabrese R, Franceschi C, Bürkle A, Caiafa P. Reconfiguration of DNA methylation in aging. Mech Ageing Dev 151: 60‐70, 2015.
 642.Zane AC, Reiter DA, Shardell M, Cameron D, Simonsick EM, Fishbein KW, Studenski SA, Spencer RG, Ferrucci L. Muscle strength mediates the relationship between mitochondrial energetics and walking performance. Aging Cell 16: 461‐468, 2017.
 643.Zhang BB, Zhou G, Li C. AMPK: An emerging drug target for diabetes and the metabolic syndrome. Cell Metab 9: 407‐416, 2009.
 644.Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352: 1436‐1443, 2016.
 645.Zhang WB, Aleksic S, Gao T, Weiss EF, Demetriou E, Verghese J, Holtzer R, Barzilai N, Milman S. Insulin‐like Growth Factor‐1 and IGF binding proteins predict all‐cause mortality and morbidity in older adults. Cells 9: 1368, 2020.
 646.Zhang WB, Sinha DB, Pittman WE, Hvatum E, Stroustrup N, Pincus Z. Extended twilight among isogenic C. elegans causes a disproportionate scaling between lifespan and health. Cell Syst 3: 333‐345.e334, 2016.
 647.Zhang Y, Bokov A, Gelfond J, Soto V, Ikeno Y, Hubbard G, Diaz V, Sloane L, Maslin K, Treaster S, Réndon S, van Remmen H, Ward W, Javors M, Richardson A, Austad SN, Fischer K. Rapamycin extends life and health in C57BL/6 mice. J Gerontol A Biol Sci Med Sci 69: 119‐130, 2014.
 648.Zhang Y, Unnikrishnan A, Deepa SS, Liu Y, Li Y, Ikeno Y, Sosnowska D, Van Remmen H, Richardson A. A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1. Redox Biol 11: 30‐37, 2017.
 649.Zheng Y, Kong J, Li Q, Wang Y, Li J. Role of miRNAs in skeletal muscle aging. Clin Interv Aging 13: 2407‐2419, 2018.
 650.Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xu X. Sirtuin 1‐mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes 61: 217‐228, 2012.
 651.Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age‐related chronic diseases. Curr Opin Clin Nutr Metab Care 17: 324‐328, 2014.
 652.Zhu Y, Tchkonia T, Fuhrmann‐Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL. Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors. Aging Cell 15: 428‐435, 2016.

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Article Title: Physiological Systems in Promoting Frailty
 

How to Cite

Laís R. Perazza, Holly M. Brown‐Borg, LaDora V. Thompson. Physiological Systems in Promoting Frailty. Compr Physiol 2022, 12: 3575-3620. doi: 10.1002/cphy.c210034