News & Views | Published:


Genetic rejuvenation of old muscle

Nature volume 506, pages 304305 (20 February 2014) | Download Citation

In advanced age, the stem cells responsible for muscle regeneration switch from reversible quiescence to irreversible senescence. Targeting a driver of senescence revives muscle stem cells and restores regeneration. See Article p.316

One of the telltale signs of advanced ageing is loss of skeletal-muscle mass and strength, a phenomenon known as sarcopenia. Muscle strength is inversely correlated with mortality in old populations1,2, and the decline in strength is attributable to the decreased regenerative capacity of muscle stem cells, called satellite cells, with age. Whether this decline is caused by cell-intrinsic and/or environmental alterations has remained unclear. On page 316 of this issue, Sousa-Victor et al.3 shed light on this debate by uncovering intrinsic aspects of age-related satellite-cell dysfunction that account for the loss of muscle maintenance (homeostasis) and regeneration. This study also provides a potential strategy for satellite-cell rejuvenation that could benefit geriatric individuals and those with progeria, a disorder in which cells age prematurely.

Satellite cells reside in close proximity to large muscle cells called myofibres. They are responsible for post-natal muscle growth, as well as regeneration after injury. Because under normal conditions skeletal muscles exhibit low turnover, satellite cells exist in a reversible quiescent state. Once stimulated by homeostatic demand or damage, they become activated and re-enter the cell cycle to generate muscle progenitor cells — which differentiate and fuse to form new fibres — or self-renew to replenish the stem-cell population (Fig. 1a).

Figure 1: Old age disrupts muscle regeneration.
Figure 1

a, Satellite cells, a type of muscle stem cell, remain quiescent under normal conditions. After muscle damage, satellite cells become activated and re-enter the cell cycle to produce muscle progenitor cells that regenerate new muscle fibres. They also self-renew to replenish the stem-cell population. b, Sousa-Victor et al.3 report that during ageing, geriatric satellite cells lose their reversible quiescent state owing to derepression of the gene encoding p16INK4a, a regulator of cellular senescence. Instead, they adopt a senescent-like state (becoming pre-senescent cells), which impairs the regeneration process, including activation, proliferation and self-renewal.

Satellite cells actively maintain their quiescent state through transcriptional, post-transcriptional and post-translational mechanisms4,5. Dysregulation of quiescence often leads to stem-cell exhaustion and failure of regeneration6. Evidence suggests7 that extrinsic changes in the milieu surrounding satellite cells contribute to the cells' well-documented decline during ageing, and that exposure to a youthful environment can reverse this process. Notably, fibroblast growth factor-2 produced by neighbouring cells in an aged environment disrupts satellite-cell quiescence and self-renewal8. So far, few studies have investigated the intrinsic changes in satellite cells during ageing5,9 or the potential role of such changes in regenerative decline.

To address these issues, Sousa-Victor and colleagues first compared muscle properties in mice of various ages and established that features of sarcopenia appeared mainly in mice of geriatric age (at 28 months and thereafter) or in a mouse model of progeria. Notably, on the induction of muscle injury by a toxin, the authors observed a sharp decline in the regenerative capacity of satellite cells in geriatric, sarcopenic mice compared with old, non-sarcopenic mice. This phenomenon cannot be explained by a reduced satellite-cell pool, because the number of these cells was comparable in both groups of mice.

Next, the authors conducted a series of experiments in which satellite cells from geriatric and old animals were transplanted into young mice, and this definitively proved that the regenerative decline of geriatric muscle is due to changes intrinsic to satellite cells, independent of the host environment. Intriguingly, geriatric satellite cells exhibited a cell-cycle block and defective activation in response to injury both in situ and after transplantation, indicating a failure to maintain a reversible state of quiescence.

What factors could be responsible for this loss of quiescence? Through comparative analyses of the gene-expression programs of quiescent satellite cells of different ages, Sousa-Victor and co-workers narrowed down the list of candidates to the tumour-suppressor protein p16INK4a, which is regarded as a master regulator of cellular senescence. In a series of experiments, the authors found evidence to support a link between p164 derepression and defective satellite-cell activation.

In a mouse model that underwent successive rounds of injury, the authors observed a depletion of self-renewing geriatric satellite cells over time, whereas normal satellite cells continued to self-renew. The pressure to proliferate in response to injury drove geriatric satellite cells into full-blown senescence, as evidenced by the expression of several classic markers of senescence. This correlated with reduced levels of phosphorylated retinoblastoma (Rb) protein, and with reduced expression of genes regulated by Rb and the transcription factor E2F, suggesting that the well-defined p16INK4a/Rb/E2F signalling axis drives the conversion to senescence.

Sousa-Victor et al. genetically silenced p16INK4a expression and found that this restored self-renewal and proliferation in geriatric satellite cells. These results show that p16INK4a derepression in geriatric and progeric satellite cells leads to the loss of the reversible quiescent state and to the adoption of a senescent-like state, which impairs regeneration (Fig. 1b). The relevance of this work to human health is strengthened by Sousa-Victor and co-workers' finding that the p16INK4a/Rb/E2F axis drives dysfunction in geriatric human satellite cells similarly to the way it does in mice.

Although p16INK4a expression during ageing has been shown to impair regeneration in blood, neural and pancreatic tissues6, it has never been reported in aged satellite cells, despite previous gene-profiling studies4. The use of a clearly defined sarcopenic geriatric population may be the key to this discovery, which itself represents an important addition to a growing body of evidence10,11 showing that p16INK4a-induced senescence limits the regenerative capacity of stem cells during ageing and contributes to age-related pathologies. Because p16INK4a expression is also a barrier to stem-cell reprogramming12,13, this research increases the potential benefits of transiently inactivating p16INK4a for regenerative medicine.

Sousa-Victor and colleagues' study provides a new view of satellite-cell ageing, but the results inevitably raise further questions. For example, what triggers the p16INK4a/Rb/E2F senescence pathway during ageing? A recent study9 found no evidence of significant accumulation of DNA damage in old satellite cells compared with young ones. Could it be that p16INK4a is derepressed owing to signals from neighbouring senescent cells, such as low-level systemic inflammation or elevated levels of reactive oxygen species?

Because satellite cells are not a uniform population, it is possible that a sub-population is more susceptible or immune to the quiescent-to-senescent switch. Along this line, it will be interesting to determine whether geriatric satellite cells that are activated on injury maintain full 'stemness'. Could any as-yet-unidentified, age-associated environmental factors be neutralized to postpone the p16INK4a induction in satellite cells of sarcopenic muscle? And, if so, could physical exercise delay p16INK4a induction?

Finally, this study presents yet another addition to the list of potential strategies to improve the regenerative capacity of aged tissue11,14,15. It may be worth considering whether the benefits of transiently reducing tumour-suppressor levels in stem cells outweigh the associated risks, in the context of preventing an age-related decline in regenerative potential. Whether these strategies can be safely implemented in the clinic to maximize human health span deserves thorough investigation in the near future.


  1. 1.

    et al. Br. Med. J. 337, a439 (2008).

  2. 2.

    et al. Eur. J. Prev. Cardiol. (2012).

  3. 3.

    et al. Nature 506, 316–321 (2014).

  4. 4.

    & Nature Rev. Mol. Cell Biol. 14, 329–340 (2013).

  5. 5.

    et al. Cell Rep. 4, 189–204 (2013).

  6. 6.

    & Nature Rev. Genet. 9, 115–128 (2008).

  7. 7.

    , , , & Cold Spring Harb. Symp. Quant. Biol. 76, 101–111 (2011).

  8. 8.

    , , & Nature 490, 355–360 (2012).

  9. 9.

    et al. PLoS ONE 8, e63528 (2013).

  10. 10.

    , , , & Cell 153, 1194–1217 (2013).

  11. 11.

    et al. Nature 479, 232–236 (2011).

  12. 12.

    et al. Nature 460, 1136–1139 (2009).

  13. 13.

    et al. Aging Cell 11, 41–50 (2012).

  14. 14.

    , , , & Cell Stem Cell 7, 198–213 (2010).

  15. 15.

    et al. Cell 155, 778–792 (2013).

Download references

Author information


  1. Mo Li and Juan Carlos Izpisua Belmonte are in the Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.

    • Mo Li
    •  & Juan Carlos Izpisua Belmonte


  1. Search for Mo Li in:

  2. Search for Juan Carlos Izpisua Belmonte in:

Corresponding author

Correspondence to Juan Carlos Izpisua Belmonte.

About this article

Publication history



Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing