The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals
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Summary: Age‐related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high‐ and low‐functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low‐functioning elderly (LFE) participants when compared to young and high‐functioning elderly participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in cytochrome c oxidase activity. Levels of key metabolic regulators, SIRT3 and PGC‐1α, were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects; however, no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.
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Aging is associated with mitochondrial dysfunction, insulin resistance, oxidative stress, and altered myokine-adipokine signaling, which impair ability to adapt to energetic demands and stressors.
“At the cellular level, aging is associated with mitochondrial dysfunction, insulin resistance, oxidative stress, and altered myokine–adipokine signaling, which collectively impair the body’s ability to adapt to energetic demands and external stressors [2,3].”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [2]
The Introduction and Discussion link aging in skeletal muscle to mitochondrial dysfunction and oxidative damage; the Abstract says impaired mitochondrial function may contribute to declining muscle performance. Our copy does not support the sentence’s additional claims about insulin resistance, altered myokine–adipokine signaling, or a collective impairment in adapting to external stressors. The cited passages have no page numbers in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRecent studies investigating whether mitochondrial quality control is influenced by aging have produced inconclusive results.
“Recent studies have investigated whether mitochondrial quality control is influenced by aging, but the results are not conclusive and remain to be elucidated (1,2,25,35,36).”
From Chronological Age Does not Influence<i>Ex-vivo</i>Mitochondrial Respiration and Quality Control in Skeletal Muscle (2016) · cites this paper as [1]
The Introduction and Discussion say that studies disagree about age-related changes in skeletal-muscle mitochondrial properties and that the extent of mitochondrial decline remains controversial. The paper also examines fusion and fission pathways involved in maintaining mitochondrial integrity, but it does not establish that findings on mitochondrial quality control as a whole are inconclusive. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSome studies report decreased or unchanged Drp1 content in skeletal muscle of older individuals.
“With respect to Drp1 expression, some studies report a decreased (Distefano et al., 2017) or an unchanged (Joseph et al., 2012) Drp1 content in skeletal muscle of older individuals.”
From Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging ( <scp>SOMMA</scp> ) (2024) · cites this paper as Joseph et al., 2012
Normal ageing is associated with a trend for a decrease in PGC-1α expression.
“We found that normal ageing is associated with a trend for a decrease in PGC‐1α expression, which is a finding consistent with previous studies (Baker et al. 2006; Chabi et al. 2008; Joseph et al. 2012).”
From Parkin overexpression protects from ageing‐related loss of muscle mass and strength (2019) · cites this paper as Joseph et al. 2012
Joseph et al. showed that the fusion protein OPA1 was decreased in older individuals compared to young subjects, while MFN2, FIS1, and DRP1 proteins remained the same.
“Joseph et al. (1) showed that the fusion protein OPA1 was decreased in older individuals when compared to young subjects while MFN2, FIS1, and DRP1 proteins remained the same.”
From Chronological Age Does not Influence<i>Ex-vivo</i>Mitochondrial Respiration and Quality Control in Skeletal Muscle (2016) · cites this paper as [1]
Skeletal muscle from sedentary older adults exhibits reduced mitochondrial abundance and oxidative capacity.
“Skeletal muscle from sedentary older adults exhibits reduced mitochondrial abundance and oxidative capacity.”
From Combined Training Enhances Skeletal Muscle Mitochondrial Oxidative Capacity Independent of Age (2015) · cites this paper as [3]
Aging leads to increased occurrence of mitochondrial fission, aligning with fragmented mitochondrial structures commonly observed in skeletal muscle of aged rodents.
“Several studies have demonstrated that aging leads to an increased occurrence of mitochondrial fission, which aligns with the fragmented mitochondrial structures commonly observed in the skeletal muscle of aged rodents [58].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [58]
Reduced expression levels of OPA1 and MFN2 have been described in the skeletal muscle of elderly individuals.
“For instance, reduced expression levels of OPA1 (71) and MFN2 (83) have been described in the skeletal muscle of elderly individuals.”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [71]
PGC-1α, a master transcriptional regulator of mitochondrial biogenesis, is reduced at both mRNA and protein levels in aged skeletal muscle.
“PGC-1α, a master transcriptional regulator of mitochondrial biogenesis, has been shown to be reduced at both mRNA and protein levels in aged skeletal muscle (71, 72).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [71]
In humans, studies have reported decreased or unchanged Drp1 content in skeletal muscle of old individuals.
“The literature in humans also contains conflicting data, with some studies reporting a decreased [58] or an unchanged [59] Drp1 content in skeletal muscle of old individuals.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [59]
In humans, Mfn2 expression in aged skeletal muscle is reported as decreased, similar, or higher.
“In humans, while Mfn2 expression was decreased in aged skeletal muscle in one study [60], others have reported either similar [56,58,59,61] or even higher Mfn2 content in aged skeletal muscles [61].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [59]
DNA oxidative damage is associated with impairments in bioenergetics and key defects in mitochondrial quality control processes including biogenesis, morphology, and autophagy.
“A growing body of evidence indicates DNA oxidative damage is also associated with impairments in bioenergetics and key defects in mitochondrial quality control processes including biogenesis, morphology, and autophagy.(Joseph, Adhihetty, Buford, Wohlgemuth, Lees, Nguyen, Aranda, Sandesara, Pahor, and Manini 2012;Short, Bigelow, Kahl, Singh, Coenen-Schimke, Raghavakaimal, and Nair 2005b)”
From Successful aging: Advancing the science of physical independence in older adults (2015) · cites this paper as Joseph et al. 2012
PGC-1α protein and its downstream molecular targets are reduced in aging animals and humans.
“PGC-1α protein and its downstream molecular targets are reduced in aging animals (Baker, Betik, Krause, and Hepple 2006) and humans.(Joseph, Adhihetty, Buford, Wohlgemuth, Lees, Nguyen, Aranda, Sandesara, Pahor, and Manini 2012;Safdar, Hamadeh, Kaczor, Raha, and Tarnopolsky 2010)”
From Successful aging: Advancing the science of physical independence in older adults (2015) · cites this paper as Joseph et al. 2012
Muscle mitochondria are important regulators of muscle size.
“Together, these observations support for the idea that muscle mitochondria are important regulators of muscle size.”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [62]
Muscles of aged rodents and humans have a greater overall rate of fission versus fusion and lower Opa1 levels than younger muscles.
“muscles of aged rodents and humans have a greater overall rate of fission vs. fusion (55, 62) and lower levels of the fusion protein Opa1 (62) as compared with younger muscles.”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [62]
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“With respect to Drp1 expression, some studies report a decreased (Distefano et al., 2017 ) or an unchanged (Joseph et al., 2012 ) Drp1 content in skeletal muscle of older individuals.”
Background
- Authors
- Joseph, A., Adhihetty, P. J., Buford, T. W., Wohlgemuth, S. E., Lees, H. A., Nguyen, L. M. ‐., Aranda, J. M., Sandesara, B. D., Pahor, M., Manini, T. M., Marzetti, E., & Leeuwenburgh, C.
- Affiliations
- University of Florida (US)
- University of Florida Health (US)
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Leeuwenburgh, Christiaan
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-07-09
- Volume
- 11
- Issue
- 5
- Pages
- 801-809
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3444680
- OpenAlex
- W2134036439
- Cited by
- 395
- References
- 45
- Citations by year
- 2026: 23 · 2025: 37 · 2024: 38 · 2023: 26 · 2022: 38 · 2021: 41 · 2020: 28 · 2019: 23 · 2018: 32 · 2017: 20 · 2016: 18 · 2015: 22 · 2014: 25 · 2013: 17 · 2012: 6
- FWCI
- 9.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
- Funders
- University of Florida (1 P30 AG028740)
- National Institutes of Health (UL1TR000064)
- National Institute on Aging (P30AG028740)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- sarcopenia, mitochondrial dysfunction, mitochondrial biogenesis, skeletal muscle aging, sedentary older adults, physical performance, mitochondrial respiration, cytochrome c oxidase, SIRT3, PGC-1α, OPA1, mitochondrial fusion, mitochondrial protein import, Tom22, muscle atrophy, frailty, Short Physical Performance Battery
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Female, Humans, Male, Middle Aged, Mitochondria, Muscle, Muscle, Skeletal, MAP Kinase Signaling System, Mitochondrial Proteins, AMP-Activated Protein Kinases, Young Adult, Sarcopenia, Sedentary Behavior
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