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Cited by 15Nutrition and Health in AgingMuscle Physiology and DisordersAdipose Tissue and Metabolism

Targeting Intramyocellular Lipids to Improve Aging Muscle Function

Open access
Russ, David W., Manickam, Ravikumar, Tipparaju, Srinivas M.·2025·Lipids in Health and Disease
DOI 10.1186/s12944-025-02622-6PMC PMC12125834
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Abstract

Decline of skeletal muscle function in old age is a significant contributor to reduced quality of life, risk of injury, comorbidity and disability and even mortality. While this loss of muscle function has traditionally been attributed to sarcopenia (loss of muscle mass), it is now generally appreciated that factors other than mass play a significant role in age-related muscle weakness. One such factor gaining increased attention is the ectopic accumulation of lipids in skeletal muscle, in particular, intramyocellular lipids (IMCLs). It has been appreciated for some time that metabolic flexibility of several tissues/organs declines with age and may be related to accumulation of IMCLs in a "vicious cycle" whereby blunted metabolic flexibility promotes accumulation of IMCLs, which leases to lipotoxicity, which can then further impair metabolic flexibility. The standard interventions for addressing lipid accumulation and muscle weakness remain diet (caloric restriction) and exercise. However, long-term compliance with both interventions in older adults is low, and in the case of caloric restriction, may be inappropriate for many older adults. Accordingly, it is important, from a public health standpoint, to pursue potential pharmacological strategies for improving muscle function. Because of the success of incretin-analog drugs in addressing obesity, these medications may potentially reduce IMCLs in aging muscles and thus improve metabolic flexibility and improve muscle health. A contrasting potential pharmacological strategy for addressing these issues might be to enhance energy provision to stimulate metabolism by increasing NAD + availability, which is known to decline with age and has been linked to reduced metabolic flexibility. In this narrative review, we present information related to IMCL accumulation and metabolic flexibility in old age and how the two major lifestyle interventions, caloric restriction and exercise, can affect these factors. Finally, we discuss the potential benefits and risks of select pharmacologic interventions in older adults.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that age-related muscle weakness is driven partly by intramyocellular lipid (IMCL) accumulation and reduced metabolic flexibility, not just loss of muscle mass. It evaluates exercise, caloric restriction, incretin analogs, PCSK9 inhibition, and NAD+-directed strategies, concluding that NAD+ activation via NAMPT is a promising but largely preclinical alternative to incretin drugs in older adults.

Key findings

  • Age-related muscle weakness contributes to >50% of all chronic conditions in people over 50 and may account for 1.5% (>$40 billion) of total U.S. healthcare expenditures; loss of muscle performance has a greater negative impact on older adults than loss of mass.
  • IMCLs accumulate with aging and disuse even without insulin resistance and are linked to lipotoxicity, inflammation, oxidative injury, impaired neuromuscular junction maintenance, and reduced metabolic flexibility; the Athlete’s Paradox shows high IMCLs can be nonpathogenic when metabolic flexibility is preserved.
  • Exercise and caloric restriction can affect IMCLs, but caloric restriction effects are mixed (increases, decreases, no change), typically involve 20%–50% reductions in intake, and may risk lean/muscle mass loss; incretin analogs may reduce IMCLs, but a cited review found only 4 of 24 studies involved participants with mean age ≥60 years, and the oldest sample (68 years) had only 9 participants.
  • NAD+ declines with aging; the NAMPT activator P7C3 increased NAD+, voluntary strength, muscle contractility, and realigned pro-/anti-inflammatory lipids in a murine model of type 2 diabetes, whereas human NAD+ precursor studies did not improve muscle function or increase muscle NAD+.

Methods

  • Narrative review; no systematic search, meta-analysis, or primary data collection is described.
  • Synthesizes human and animal/preclinical literature on IMCL accumulation, metabolic flexibility, lifestyle interventions (exercise, caloric restriction), and pharmacologic strategies (incretin analogs, PCSK9 inhibition, NAD+-directed medications).
  • Main analysis is narrative synthesis and hypothesis generation, including proposed mechanisms for NAMPT activation in aging muscle.

Limitations

  • Stated: the cause-and-effect relationship between IMCL accumulation and mitochondrial dysfunction remains equivocal; incretin drug application in aging is limited with a lack of human clinical trials; most anti-obesity drug studies are in obesity/diabetes rather than aged populations; NAD+ data are mostly preclinical; human NAD+ precursor trials have not shown improved muscle function or increased muscle NAD+.
  • Evident: as a narrative review, it lacks systematic search, risk-of-bias assessment, and quantitative synthesis; the proposed benefits of NAMPT activation for aging muscle remain hypotheses not directly tested in aged humans.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s12944-025-02622-6

Cites

182 of 182 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 132 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Loss of muscle size cannot explain most, or even a major portion, of the impaired muscle performance and physical function observed in old age.

    “data emerged suggesting that loss of muscle size could not explain most, or even a major portion, of the impaired muscle performance (force, power, etc.) and physical function observed in old age [4, 18–20]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Brown M, Sinacore DR, Host HH. The relationship of strength to function in the older adult. J Gerontol Biol Sci Med Sci. 1995;50(Spec No):55– 9. source

      Not checked in the free run.

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      Not checked in the free run.

  • Findingcitation

    Increased intramyocellular lipids are predictive of losses of physical function, such as gait speed, that are associated with increased morbidity and mortality.

    “Longitudinal studies indicate that increased IMCLs are predictive of losses of physical function (e.g., gait speed) that are associated with increased rates of morbidity and mortality (Beavers, 2013) [54].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Beavers, 2013

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  • Findingcitation

    Fit, well-trained aerobic athletes exhibit high levels of intramyocellular lipids/lipid droplets with no lipotoxicity or loss of muscle function.

    “fit, well-trained aerobic athletes exhibit high levels of IMCLs/LDs with no lipotoxicity or loss of muscle function [73–75].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [73] Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001;86(12):5755–61. source

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  • Findingcitation

    Excess intramyocellular lipids are associated with impaired muscle function in Type 2 diabetes and obesity.

    “excess IMCLs, largely in the form of lipid droplets (LDs), are associated with impaired muscle function in conditions such as Type 2 diabetes and obesity”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] Ostler JE, Maurya SK, Dials J, Roof SR, Devor ST, Ziolo MT, et al. Effects of insulin resistance on skeletal muscle growth and exercise capacity in type 2 diabetic mouse models. Am J Physiol Endocrinol Metab. 2014;306(6):E592–605. source

      Not checked in the free run.

    • cites [59] Handy RM, Holloway GP. Insights into the development of insulin resistance: unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology. Front Physiol. 2023;14:1151389. source

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  • Findingcitation

    Aging and disuse, even in the absence of insulin resistance, are associated with increased intramyocellular lipids.

    “However, aging and disuse, even in the absence of insulin resistance are associated with increased IMCLs [57, 60–63].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [57] Carter CS, Justice JN, Thompson L. Lipotoxicity, aging, and muscle contractility: does fiber type matter? Geroscience. 2019;41(3):297–308. source

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  • May combine two claims. 32
  • Classified as probably not a substantial claim. 7

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    Findingcitation

    Ectopic deposition of lipids in muscle is associated with inflammation, oxidative injury, insulin resistance and disruption of several cell functions, a condition referred to as lipotoxicity.

    “This ectopic deposition of lipids in muscle is a hallmark of pathology in several conditions and is associated with inflammation, oxidative injury, insulin resistance and disruption of several cell functions, a condition referred to as lipotoxicity [55–57].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [55] Engin AB. What is lipotoxicity?? Adv Exp Med Biol. 2017;960:197–220. source

      Not checked in the free run.

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    • cites [57] Carter CS, Justice JN, Thompson L. Lipotoxicity, aging, and muscle contractility: does fiber type matter? Geroscience. 2019;41(3):297–308. source

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    Findingcitation

    In carnitine palmitoyltransferase 1B knockout mice, intramyocellular lipid accumulation may not directly induce insulin resistance, but the animals exhibited muscle injury, disrupted metabolism and functional impairment that were partially ameliorated by a low-fat diet.

    “A set of interesting experiments in transgenic mice (carnitine palmitoyltransferase 1B knockout) have suggested that IMCL accumulation may not directly induce insulin-resistance, but even these animals’ exhibited markers of muscle injury, disrupted metabolism and functional impairment, which were partially ameliorated by a low-fat diet [67–69].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [67] Warfel JD, Bermudez EM, Mendoza TM, Ghosh S, Zhang J, Elks CM, et al. Mitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice. Sci Rep. 2016;6:37941. source

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    • cites [68] Warfel JD, Vandanmagsar B, Wicks SE, Zhang J, Noland RC, Mynatt RL. A low fat diet ameliorates pathology but retains beneficial effects associated with CPT1b knockout in skeletal muscle. PLoS ONE. 2017;12(12):e0188850. source

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    • cites [69] Wicks SE, Vandanmagsar B, Haynie KR, Fuller SE, Warfel JD, Stephens JM, et al. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. Proc Natl Acad Sci U S A. 2015;112(25):E3300–9. source

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    Findingcitation

    Aging is generally associated with a reduction in overall physical activity.

    “Aging is generally associated with a reduction in overall physical activity [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Manini TM. Energy expenditure and aging. Ageing Res Rev. 2010;9(1):1–11. source

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    Findingcitation

    Intramyocellular lipids are reduced less following exercise in older versus young adults, though later in the recovery period the levels are similar.

    “IMCLs are reduced less following exercise in older vs. young adults, though later in the recovery period, the IMCL levels are similar [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Tsintzas K, Stephens FB, Snijders T, Wall BT, Cooper S, Mallinson J, et al. Intramyocellular lipid content and lipogenic gene expression responses following a single bout of resistance type exercise differ between young and older men. Exp Gerontol. 2017;93:36–45. source

      Not checked in the free run.

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    Findingcitation

    Exercise enhances metabolic flexibility of muscle, promoting complete oxidation of palmitate.

    “Exercise has also been found to enhance metabolic flexibility of muscle [107], promoting the complete oxidation of palmitate”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Laye MJ, Rector RS, Borengasser SJ, Naples SP, Uptergrove GM, Ibdah JA, et al. Cessation of daily wheel running differentially alters fat oxidation capacity in liver, muscle, and adipose tissue. J Appl Physiol. 2009;106(1):161–8. source

      Not checked in the free run.

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    Findingcitation

    Muscle β-oxidation increases in response to a high-fat diet, but excessive lipid content or duration can exceed this capacity, leading to ectopic lipid accumulation and impaired lipid metabolism.

    “muscle β-oxidation increases in response to a high-fat diet (HFD) [83–86], although excessive lipid content or duration of such diets can exceed this capacity, leading to ectopic lipid accumulation and impaired lipid metabolism [87–91].”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [83] Dasari S, Newsom SA, Ehrlicher SE, Stierwalt HD, Robinson MM. Remodeling of skeletal muscle mitochondrial proteome with high-fat diet involves greater changes to beta-oxidation than electron transfer proteins in mice. Am J Physiol Endocrinol Metab. 2018;315(4):E425–34. source

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    • cites [84] Garcia-Roves P, Huss JM, Han DH, Hancock CR, Iglesias-Gutierrez E, Chen M, et al. Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci U S A. 2007;104(25):10709–13. source

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    • cites [86] Miller WC, Bryce GR, Conlee RK. Adaptations to a high-fat diet that increase exercise endurance in male rats. J Appl Physiology: Respiratory Environ Exerc Physiol. 1984;56(1):78–83. source

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    • cites [89] Messa GAM, Piasecki M, Hurst J, Hill C, Tallis J, Degens H. The impact of a high-fat diet in mice is dependent on duration and age, and differs between muscles. J Exp Biol. 2020;223(Pt 6). source

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    • cites [90] Shortreed KE, Krause MP, Huang JH, Dhanani D, Moradi J, Ceddia RB, et al. Muscle-specific adaptations, impaired oxidative capacity and maintenance of contractile function characterize diet-induced obese mouse skeletal muscle. PLoS ONE. 2009;4(10):e7293. source

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      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    With imposed muscle disuse, normal resting lipid oxidation is disrupted and these conditions are associated with increased intramyocellular lipids.

    “With imposed muscle disuse (e.g., bedrest, immobilization), normal resting lipid oxidation is disrupted and these conditions are also associated with increased IMCL [62, 72, 82].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] Vigelso A, Gram M, Dybboe R, Kuhlman AB, Prats C, Greenhaff PL, et al. The effect of age and unilateral leg immobilization for 2 weeks on substrate utilization during moderate-intensity exercise in human skeletal muscle. J Physiol. 2016;594(8):2339–58. source

      Not checked in the free run.

    • cites [72] Black MN, Wilkinson JA, Webb EK, Kamal M, Bahniwal R, McGlory C, et al. Two weeks of single-leg immobilization alters intramyocellular lipid storage characteristics in healthy, young women. J Appl Physiol. 2021;130(4):1247–58. source

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    Findingcitation

    Exercise and nutrition affect the supply and demand aspects of metabolism and have been shown to influence intramyocellular lipid levels in aging and obesity.

    “they affect the supply and demand aspects of metabolism, respectively, and have been shown to influence IMCL levels in both aging and obesity [59, 97, 99, 101, 102].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [59] Handy RM, Holloway GP. Insights into the development of insulin resistance: unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology. Front Physiol. 2023;14:1151389. source

      Not checked in the free run.

    • cites [97] Fritzen AM, Lundsgaard AM, Kiens B. Tuning fatty acid oxidation in skeletal muscle with dietary fat and exercise. Nat Rev Endocrinol. 2020;16(12):683–96. source

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    • cites [101] Kiens B, Alsted TJ, Jeppesen J. Factors regulating fat oxidation in human skeletal muscle. Obes Reviews: Official J Int Association Study Obes. 2011;12(10):852–8. source

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    • cites [102] Corpeleijn E, Saris WH, Blaak EE. Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle. Obes Reviews: Official J Int Association Study Obes. 2009;10(2):178–93. source

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  • May combine two claims.

    Findingreasoning

    Both life-long exercise and exercise initiated at older ages can positively affect muscle performance and muscle lipids in human and animal models.

    “both life-long exercise and exercise initiated at older ages can positively affect both muscle performance and muscle lipids in both human and animal models.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    A long-term calorie-restricted diet extends lifespan and reduces age-related physiological impairments in a variety of organisms.

    “a long-term calorie-restricted diet has been recognized for many years as a way to extend lifespan and reduce age-related physiological impairments in a variety of organisms [114–116].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [114] Most J, Gilmore LA, Smith SR, Han H, Ravussin E, Redman LM. Significant improvement in cardiometabolic health in healthy Nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance. Am J Physiol Endocrinol Metab. 2018;314(4):E396–405. source

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    • cites [115] Weinheimer EM, Sands LP, Campbell WW. A systematic review of the separate and combined effects of energy restriction and exercise on fat-free mass in middle-aged and older adults: implications for sarcopenic obesity. Nutr Rev. 2010;68(7):375–88. source

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    • cites [116] Xie WQ, Xiao WF, Tang K, Wu YX, Hu PW, Li YS, et al. Caloric restriction: implications for sarcopenia and potential mechanisms. Aging. 2020;12(23):24441–52. source

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    Findingcitation

    Older adults exhibit an elevated respiratory exchange ratio during resting metabolic rate assessment, reflecting greater carbohydrate versus lipid metabolism, and respiratory exchange ratio is positively associated with weight gain in older adults.

    “Older adults exhibit an elevated respiratory exchange ratio (reflecting greater CHO vs. lipid metabolism) during assessment of resting metabolic rate, and respiratory exchange ratio is positively associated with weight (fat) gain in older adults (JC Seidell, 1992).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites JC Seidell, 1992

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    Findingnone given

    Muscle disuse leads to increased muscle lipid deposition and loss of muscle performance.

    “muscle disuse leads to increased muscle lipid deposition and loss of muscle performance (weakness, fatigue, insulin resistance, etc.).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    There are concerns that PCSK9 inhibition might promote intrahepatic lipid accumulation.

    “there are some concerns that PCSK9 inhibition might promote intrahepatic lipid accumulation [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Ioannou GN, Lee SP, Linsley PS, Gersuk V, Yeh MM, Chen YY, et al. Pcsk9 deletion promotes murine nonalcoholic steatohepatitis and hepatic carcinogenesis: role of cholesterol. Hepatol Commun. 2022;6(4):780–94. source

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    Findingcitation

    Incretin analog medications significantly improve the efficacy and effectiveness of pharmacological approaches to weight loss.

    “they have been found to significantly improve the efficacy and effectiveness of pharmacological approaches to weight loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Reduced muscle NAD+ is observed with aging, attributed to both increased consumption for specific biochemical processes and reduced synthesis.

    “Reduced muscle NAD + is observed with aging, attributed to both increased consumption for specific biochemical processes and reduced synthesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Administration of P7C3, a NAMPT activator, increases NAD+, enhances voluntary strength and muscle contractility, and realigns pro- and anti-inflammatory lipids in a murine model of type 2 diabetes to better approximate healthy control mice.

    “We have found that administration of 3,6-dibromo-α-[(phenylamino)methyl]-9 H-carbazol-9-ethanol (P7C3), a NAMPT activator, increases NAD+, enhances voluntary strength and muscle contractility [145] (in response to direct stimulation), and realigns pro-and anti-inflammatory lipids in a murine model of type 2 diabetes to better approximate those of healthy control mice”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Manickam R, Tur J, Badole SL, Chapalamadugu KC, Sinha P, Wang Z, et al. Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators. J Cachexia Sarcopenia Muscle. 2022;13(2):1177–96. source

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    Findingcitation

    Weight regain following caloric restriction interventions appears to preferentially favor increased fat mass versus lean/muscle mass, potentially due to altered lipid oxidation.

    “weight regain following CR interventions appears to preferentially favor increased fat mass vs. lean/muscle mass [123, 133], potentially due to altered lipid oxidation [134].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [123] Chmelo EA, Beavers DP, Lyles MF, Marsh AP, Nicklas BJ, Beavers KM. Legacy effects of short-term intentional weight loss on total body and thigh composition in overweight and obese older adults. Nutr Diabetes. 2016;6(4):e203. source

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    • cites [133] Calonne J, Arsenijevic D, Scerri I, Miles-Chan JL, Montani JP, Dulloo AG. Low 24-hour core body temperature as a thrifty metabolic trait driving catch-up fat during weight regain after caloric restriction. Am J Physiol Endocrinol Metab. 2019;317(4):E699–709. source

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    • cites [134] Steig AJ, Jackman MR, Giles ED, Higgins JA, Johnson GC, Mahan C, et al. Exercise reduces appetite and traffics excess nutrients away from energetically efficient pathways of lipid deposition during the early stages of weight regain. Am J Physiol Regul Integr Comp Physiol. 2011;301(3):R656–67. source

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    Findingcitation

    A recent review found only 4 of 24 studies involved participants with a mean age of at least 60 years, and the study with the oldest sample (68 years) consisted of only 9 participants.

    “a recent review paper [142] found only 4 of 24 studies involved participants with a mean age of ≥ 60 years and the study with the oldest sample (68 years) consisted of only 9 participants.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Findingcitation

    Aging and obesity/diabetes share physiological aspects including accumulation of ectopic lipids and lipotoxicity in liver, skeletal muscle and heart, as well as decreased mitochondrial number and activity.

    “A number of physiological aspects of aging are also found in obesity and diabetes (Fig. 2) including accumulation of ectopic lipids and lipotoxicity in metabolic organs such as liver, skeletal muscle and heart, as well as decreased mitochondrial number and activity [144–147].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [144] Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51(10):2944–50. source

      Not checked in the free run.

    • cites [145] Manickam R, Tur J, Badole SL, Chapalamadugu KC, Sinha P, Wang Z, et al. Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators. J Cachexia Sarcopenia Muscle. 2022;13(2):1177–96. source

      Not checked in the free run.

    • cites [146] Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, et al. Reduced mitochondrial density and increased IRS-1 Serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005;115(12):3587–93. source

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    • cites [147] Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes. 2005;54(1):8–14. source

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  • May combine two claims.

    Findingcitation

    Anti-obesity incretin-analog drugs function largely through caloric restriction with minimal effects on energy expenditure, consistent with reports that muscles do not express GLP-1 or GIP receptors.

    “they function largely through CR with minimal effects on energy expenditure, consistent with reports that muscles do not express GLP-1 or GIP receptors [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat Rev Endocrinol. 2023;19(4):201–16. source

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  • May combine two claims.

    Findingcitation

    Exercise participation among older adults is low and may be precluded or limited due to age-related co-morbidities, social and environmental barriers.

    “exercise participation among older adults is low and in a number of older adults may be precluded or limited due to age-related co-morbidities, as well as social and environmental barriers [136–140].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [136] (US) NCfHS, Health US. 2014: With Special Feature on Adults Aged 55–64. Health, Hyattsville (MD): United States; 2015.

      Not checked in the free run.

    • cites [137] Beck KL, Weeks LE, Montelpare WJ, MacDonald DJ. Identifying important factors for older adults’ physical activity participation across individual/group, structured/unstructured contexts. Eur J Ageing. 2016;13(3):209–18. source

      Not checked in the free run.

    • cites [138] Harvey JA, Chastin SF, Skelton DA. Prevalence of sedentary behavior in older adults: a systematic review. Int J Environ Res Public Health. 2013;10(12):6645–61. source

      Not checked in the free run.

    • cites [139] Jancey J, Lee A, Howat P, Clarke A, Wang K, Shilton T. Reducing attrition in physical activity programs for older adults. J Aging Phys Act. 2007;15(2):152–65. source

      Not checked in the free run.

    • cites [140] Hui EK, Rubenstein LZ. Promoting physical activity and exercise in older adults. J Am Med Dir Assoc. 2006;7(5):310–4. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Few studies of anti-obesity drug treatment directly evaluate intramyocellular lipids in humans or animals, and none were conducted in aged humans or animals; all involved models of obesity and/or Type 2 diabetes.

    “There are few studies of anti-obesity drug treatment that directly evaluate IMCLs in either humans or animals [153–156], which report either decreases or no change in IMCL. However, none of these studies were conducted in aged humans or animals, and all involved models of obesity and/or Type 2 diabetes.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [153] Watanabe T, Tamura Y, Kakehi S, Funayama T, Gastaldelli A, Takeno K, et al. Effects of sitagliptin on ectopic fat contents and glucose metabolism in type 2 diabetic patients with fatty liver: A pilot study. J Diabetes Investig. 2015;6(2):164–72. source

      Not checked in the free run.

    • cites [154] Xu F, Cao H, Chen Z, Gu H, Guo W, Lin B, et al. Short-term GLP-1 receptor agonist exenatide ameliorates intramyocellular lipid deposition without weight loss in Ob/ob mice. Int J Obes. 2020;44(4):937–47. source

      Not checked in the free run.

    • cites [155] Kakegawa T, Sugimoto K, Saito K, Yunaiyama D, Araki Y, Wada T, et al. Favorable liver and skeletal muscle changes in patients with MASLD and T2DM receiving glucagon-like peptide-1 receptor agonist: A prospective cohort study. Med (Baltim). 2024;103(23):e38444. source

      Not checked in the free run.

    • cites [156] Xiang J, Qin L, Zhong J, Xia N, Liang Y. GLP-1RA liraglutide and semaglutide improves Obesity-Induced muscle atrophy via SIRT1 pathway. Diabetes Metab Syndr Obes. 2023;16:2433–46. source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    The application of incretin-analog drugs in human and animal models of aging is limited, with a lack of human clinical trials.

    “the application of these drugs in human and animal models of aging is limited, with a lack of human clinical trials, raising potential concerns for their use in treating muscle weakness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Human studies of exogenous NAD+ precursors such as nicotinamide riboside have not shown improved muscle function nor increased muscle NAD+.

    “these approaches have not shown improved muscle function [179], nor have they shown increased muscle NAD+ [180, 181].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [179] Connell NJ, Grevendonk L, Fealy CE, Moonen-Kornips E, Bruls YMH, Schrauwen-Hinderling VB, et al. NAD+-Precursor supplementation with L-Tryptophan, nicotinic acid, and nicotinamide does not affect mitochondrial function or skeletal muscle function in physically compromised older adults. J Nutr. 2021;151(10):2917–31. source

      Not checked in the free run.

    • cites [180] Dollerup OL, Chubanava S, Agerholm M, Sondergard SD, Altintas A, Moller AB, et al. Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men. J Physiol. 2020;598(4):731–54. source

      Not checked in the free run.

    • cites [181] Jensen JB, Dollerup OL, Moller AB, Billeskov TB, Dalbram E, Chubanava S, et al. A randomized placebo-controlled trial of nicotinamide riboside and pterostilbene supplementation in experimental muscle injury in elderly individuals. JCI Insight. 2022;7:19. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Interpretationcitation

    Aging muscles lack the metabolic flexibility to process intramyocellular lipids in the way younger muscles do, leading to lipotoxicity and associated impairments.

    “we suggest a hypothesis whereby aging muscles lack the metabolic flexibility to process the IMCLs in the way that younger muscles do [62, 65, 66], leading to lipotoxicity and its associated impairments.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Vigelso A, Gram M, Dybboe R, Kuhlman AB, Prats C, Greenhaff PL, et al. The effect of age and unilateral leg immobilization for 2 weeks on substrate utilization during moderate-intensity exercise in human skeletal muscle. J Physiol. 2016;594(8):2339–58. source

      Not checked in the free run.

    • cites [65] Zhang X, Trevino MB, Wang M, Gardell SJ, Ayala JE, Han X, et al. Impaired mitochondrial energetics characterize poor early recovery of muscle mass following Hind limb unloading in old mice. J Gerontol Biol Sci Med Sci. 2018;73(10):1313–22. source

      Not checked in the free run.

    • cites [66] Tsintzas K, Stephens FB, Snijders T, Wall BT, Cooper S, Mallinson J, et al. Intramyocellular lipid content and lipogenic gene expression responses following a single bout of resistance type exercise differ between young and older men. Exp Gerontol. 2017;93:36–45. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Muscle disuse leads to a shift away from lipid toward carbohydrate oxidation similar to that seen with old age, potentially compounding deficits in metabolic flexibility and leading to further intramyocellular lipid accumulation.

    “Evidence suggests that muscle disuse leads to a shift away from lipid toward carbohydrate oxidation has been shown with muscle disuse [62, 72, 82] similar to that seen with old age, potentially compounding deficits in metabolic flexibility and leading to further IMCL accumulation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] Vigelso A, Gram M, Dybboe R, Kuhlman AB, Prats C, Greenhaff PL, et al. The effect of age and unilateral leg immobilization for 2 weeks on substrate utilization during moderate-intensity exercise in human skeletal muscle. J Physiol. 2016;594(8):2339–58. source

      Not checked in the free run.

    • cites [72] Black MN, Wilkinson JA, Webb EK, Kamal M, Bahniwal R, McGlory C, et al. Two weeks of single-leg immobilization alters intramyocellular lipid storage characteristics in healthy, young women. J Appl Physiol. 2021;130(4):1247–58. source

      Not checked in the free run.

    • cites [82] Blanc S, Normand S, Pachiaudi C, Fortrat JO, Laville M, Gharib C. Fuel homeostasis during physical inactivity induced by bed rest. J Clin Endocrinol Metab. 2000;85(6):2223–33.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Return to normal metabolism following disuse may be blunted in old age, leading to a progressive increase in intramyocellular lipids and decline in muscle performance with every episode of disuse.

    “evidence suggests that the return to normal metabolism following disuse may also be blunted in old age (impaired “metabolic elasticity” [81]), leading to a progressive increase in IMCL and decline in muscle performance with every episode of disuse.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Zhou Q, Yu L, Cook JR, Qiang L, Sun L. Deciphering the decline of metabolic elasticity in aging and obesity. Cell Metab. 2023;35(9):1661–71. e6. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Whether the effects of exercise are the same in aged individuals as opposed to adults with obesity remains equivocal and is likely influenced by long-term diet and physical activity patterns.

    “Whether these effects of exercise are the same in aged individuals, as opposed to adults with obesity remains equivocal [110–112] and is likely influenced by long-term diet and physical activity patterns.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [110] Cartee GD, Farrar RP. Muscle respiratory capacity and VO2 max in identically trained young and old rats. J Appl Physiol. 1987;63(1):257–61. source

      Not checked in the free run.

    • cites [111] Chee C, Shannon CE, Burns A, Selby AL, Wilkinson D, Smith K, et al. Relative contribution of intramyocellular lipid to Whole-Body fat oxidation is reduced with age but subsarcolemmal lipid accumulation and insulin resistance are only associated with overweight individuals. Diabetes. 2016;65(4):840–50. source

      Not checked in the free run.

    • cites [112] Latimer LE, Constantin-Teodosiu D, Popat B, Constantin D, Houchen-Wolloff L, Bolton CE et al. Whole-body and muscle responses to aerobic exercise training and withdrawal in ageing and COPD. Eur Respir J. 2022;59(5). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The cause-and-effect sequence of intramyocellular lipid accumulation and mitochondrial function remains equivocal, and the two factors are likely linked in a vicious cycle.

    “the cause and effect sequence of IMCL accumulation and mitochondrial function remains equivocal and the two factors are likely linked in a “vicious cycle [94]. ””
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Devries MC, Samjoo IA, Hamadeh MJ, McCready C, Raha S, Watt MJ, et al. Endurance training modulates intramyocellular lipid compartmentalization and morphology in skeletal muscle of lean and obese women. J Clin Endocrinol Metab. 2013;98(12):4852–62. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Impaired metabolic flexibility with aging leads to accumulation and reduced utilization of ectopic lipids that persist in skeletal muscle and may lead to increased serum free fatty acids from non-muscle sources.

    “Thus, impaired metabolic flexibility with aging leads to accumulation and reduced utilization of ectopic lipids that persist in skeletal muscle and may lead to increased serum free-fatty acids from non-muscle sources [74, 96].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Dube JJ, Amati F, Stefanovic-Racic M, Toledo FG, Sauers SE, Goodpaster BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete’s paradox revisited. Am J Physiol Endocrinol Metab. 2008;294(5):E882–8. source

      Not checked in the free run.

    • cites [96] Shaw CS, Swinton C, Morales-Scholz MG, McRae N, Erftemeyer T, Aldous A, et al. Impact of exercise training status on the fiber type-specific abundance of proteins regulating intramuscular lipid metabolism. J Appl Physiol. 2020;128(2):379–89. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    NAD+ is a key factor in metabolism of all major biomolecules and in ATP synthesis by the electron transport chain.

    “It is a key factor in metabolism of all major biomolecules (lipids, carbohydrates, amino acids) as well as ATP synthesis by the electron transport chain [164, 165]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [164] Arnold PK, Finley LWS. Regulation and function of the mammalian Tricarboxylic acid cycle. J Biol Chem. 2023;299(2):102838. source

      Not checked in the free run.

    • cites [165] Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013;17(2):162–84. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because fat mass and intramyocellular lipids tend to be positively associated, anti-obesity drugs may have potential to reduce intramyocellular lipids in aging muscle.

    “Since fat mass and IMCL tend to be positively associated, these drugs may have potential to reduce IMCL in aging muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Substrate provision is insufficient if NAMPT activity remains low, making development of pharmacological interventions to increase NAD+ via NAMPT activation a more promising strategy.

    “We suggest substrate provision is insufficient if NAMPT activity remains low, making development of pharmacological interventions to increase NAD + via NAMPT activation to be a more promising strategy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims.

    Interpretationreasoning

    Increasing NAD+ availability by NAMPT activation will normalize aging metabolic flexibility and restore muscle β-oxidation, reducing intramyocellular lipid accumulation and lipotoxicity that inhibit recovery in aged muscle.

    “We hypothesize that increasing NAD + availability by NAMPT activation will normalize aging metabolic flexibility and restore muscle β-oxidation, which will reduce the IMCL accumulation and lipotoxicity that inhibit recovery in aged muscle.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Given that aging and diabetes share several metabolic and muscular impairments, NAD+-promoting medications could have similar benefits for aging muscle, with less risk for loss of muscle mass than incretin-analog medications might pose.

    “it is not unreasonable to think NAD+ - promoting medications could have similar benefits for aging muscle, with less risk for loss of muscle mass than incretin- analog medications might pose.”
    Quote in the paperSubstantial claim
35 of 35

  • The authors state this as an assumption.

    Results of anti-obesity drugs in older adults will differ from those seen in younger adults.

    “application of the new and future generations of anti-obesity drugs to older adults should probably best proceed on the assumption that results will differ from those seen on younger adults.”

  • The paper relies on this without support.

    Long-term compliance with medications can be quite variable.

    “Long term compliance with medications can be quite variable”
2 of 2

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Authors
Russ, D. W., Manickam, R., & Tipparaju, S. M.
Affiliations
University of South Florida (US)
Corresponding author
Russ, David W.
ORCID
Venue
Lipids in Health and Disease
Publisher
Springer Science and Business Media LLC
Published
2025-05-31
Volume
24
Issue
1
Pages
197-197
ISSN
1476-511X (ISSN-L)
DOI
10.1186/s12944-025-02622-6
PMC
PMC12125834
OpenAlex
W4410922375
Semantic Scholar
216e660e4f20ed3e10f9a28df60807c420b941dc
Cited by
15
References
181
Citations by year
2026: 11 · 2025: 4
FWCI
1.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Lipids in Health and Disease (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • NIH (DK119066)
  • Saunders Endowment for Geriatric Pharmacotherapy
Topics
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
intramyocellular lipid, skeletal muscle aging, age-related muscle weakness, metabolic flexibility, lipotoxicity, sarcopenia, caloric restriction, physical activity, NAD+, ectopic fat deposition
MeSH terms
Aged, Aging, Animals, Humans, Exercise, Muscle, Skeletal, Muscle Weakness, Caloric Restriction, Lipid Metabolism, Sarcopenia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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