Exercise Counters the Age-Related Accumulation of Senescent Cells

Zhang, Xu; Englund, Davis A.; Aversa, Zaira; Jachim, Sarah K.; White, Thomas A.; LeBrasseur, Nathan K.

doi:10.1249/jes.0000000000000302

Cited by 20 publications

(17 citation statements)

References 71 publications

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“…These findings were corroborated in the soleus and we also report a significant repression of Rpl3l by MYC (adjusted P = 0.041) (see Supporting information, Table S5). This inverse pattern of Rpl3 (induction) and Rpl3l (repression) is indicative of a developmental‐ and growth‐oriented gene expression program in skeletal muscle (Chaillou, 2019; Chaillou et al., 2016; Kao et al., 2021; Lin et al, 2022; Zhang, Trapp et al., 2022; Zhang, Englund et al., 2022; Zhang, Hong et al., 2022). OKSM expression vs .…”

Section: Resultsmentioning

confidence: 99%

“…ROMO1 generates reactive oxygen species (Chung et al., 2006) and induces senescence (Chung et al., 2008). Downregulation of Romo1 m ay be beneficial in ageing muscle where senescent cells can manifest and impair adaptation (Dungan, Figueiredo et al., 2022; Dungan, Murach et al., 2022; Zhang, Englund et al., 2022; Zhang, Hong et al., 2022). ROMO1 is also a negative feedback regulator of MYC (Lee et al., 2011), and so its downregulation by MYC induction seems intuitive.…”

Section: Discussionmentioning

confidence: 99%

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A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle

Jones

Dimet²,

Haghani

et al. 2023

The Journal of Physiology

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Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from (1) a skeletal muscle‐specific in vivo Oct3/4, Klf4, Sox2 and Myc (OKSM) reprogramming‐factor expression murine model; (2) an in vivo inducible muscle‐specific Myc induction murine model; (3) a translatable high‐volume hypertrophic exercise training approach in aged mice; and (4) human exercise muscle biopsies, we collectively defined exercise‐induced genes that are common to partial reprogramming. Late‐life exercise training lowered murine DNA methylation age according to several contemporary muscle‐specific clocks. A comparison of the murine soleus transcriptome after late‐life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle‐enriched genes was conserved in skeletal muscle of long‐term exercise‐trained humans; among these was muscle‐specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC‐controlled and exercise adaptation transcriptomes, including lower muscle‐specific Melusin and reactive oxygen species‐associated Romo1. With Myc, OKSM and exercise training in mice, as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. Key points Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodelling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2 and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing. Using global gene expression analysis, we compared the effects of in vivo OKSM‐mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late‐life murine exercise training in muscle. Myc is the Yamanaka factor most induced by exercise in skeletal muscle, and so we compared the MYC‐controlled transcriptome in muscle to Yamanaka factor‐mediated and exercise adaptation mRNA landscapes in mice and humans. A single pulse of MYC is sufficient to remodel the muscle methylome. We identify partial reprogramming‐associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle

Jones

Dimet²,

Haghani

et al. 2023

The Journal of Physiology

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“…Consequently, determining the molecular mechanisms of how exercise ameliorates the aging process and increases health span is a primary point of inquiry for modern science. One key mechanism of aging is cellular senescence (3). Removal of senescent cells or prevention of cellular senescence attenuates aspects of the aging process and the progression of age-related diseases such as cardiovascular disease (CVD) and cancer (3).…”

Section: Introductionmentioning

confidence: 99%

“…One key mechanism of aging is cellular senescence (3). Removal of senescent cells or prevention of cellular senescence attenuates aspects of the aging process and the progression of age-related diseases such as cardiovascular disease (CVD) and cancer (3). Cellular senescence can be induced by stress (e.g., DNA damage) and replicative senescence.…”

Section: Introductionmentioning

confidence: 99%

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Exercise as a Therapy to Maintain Telomere Function and Prevent Cellular Senescence

Kim¹,

Ahn²,

Ying³

et al. 2023

Exercise and Sport Sciences Reviews

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Recent Advancement in Elimination Strategies and Potential Rejuvenation Targets of Senescence

Kureel,

Blair,

Sheetz

2023

Advanced Biology

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Cellular senescence is a state of exiting the cell cycle, resisting apoptosis, and changing phenotype. Senescent cells (SCs) can be identified by large, distorted morphology and irreversible inability to replicate. In early development, senescence has beneficial roles like tissue patterning and wound healing, where SCs are cleared by the immune system. However, there is a steep rise in SC number as organisms age. The issue with SC accumulation stems from the loss of cellular function, alterations of the microenvironment, and secretions of pro‐inflammatory molecules, consisting of cytokines, chemokines, matrix metalloproteinases (MMPs), interleukins, and extracellular matrix (ECM)‐associated molecules. This secreted cocktail is referred to as the senescence‐associated secretory phenotype (SASP), a hallmark of cellular senescence. The SASP promotes inflammation and displays a bystander effect where paracrine signaling turns proliferating cells into senescent states. To alleviate age‐associated diseases, researchers have developed novel methods and techniques to selectively eliminate SCs in aged individuals. Although studies demonstrated that selectively killing SCs improves age‐related disorders, there are drawbacks to SC removal. Considering favorable aspects of senescence in the body, this paper reviews recent advancements in elimination strategies and potential rejuvenation targets of senescence to bring researchers in the field up to date.

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Exercise Counters the Age-Related Accumulation of Senescent Cells

Abstract: The beneficial effects of exercise are in part mediated through the prevention and elimination of senescent cells.

Cited by 20 publications

References 71 publications

A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle

A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle

Exercise as a Therapy to Maintain Telomere Function and Prevent Cellular Senescence

Recent Advancement in Elimination Strategies and Potential Rejuvenation Targets of Senescence

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