Ageing was long thought to be inevitable, but treatment to forestall it is increasingly argued to be feasible. Of particular interest for such treatments are the ‘senescent’ cells that accumulate with age — cells that have stopped dividing and instead become seemingly dormant, in a state of arrested growth1. But it has proved challenging to isolate senescent cells, preventing researchers from fully understanding their behaviour throughout life. Writing in Nature, Moiseeva et al.2 present an approach to isolate senescent cells from mice. Their subsequent analyses reveal that the cells cause inflammation, preventing skeletal-muscle regeneration even in young animals (a setting in which the cells were previously assumed to be beneficial). The work adds weight to the idea that removing senescent cells could help to combat ageing.

Senescent cells make up a small percentage of the body, even in older individuals, and yet they cause major damage by secreting signalling proteins through a process called the senescence-associated secretory phenotype (SASP)3. The SASP induces fibrosis — the thickening and scarring of tissue — and blocks the functions of healthy neighbouring cells. As such, senescent cells are thought to contribute to many diseases and unwanted side effects of ageing.

These side effects include sarcopenia — an age-associated decline in skeletal muscle mass and function that occurs as ageing skeletal muscle becomes replaced by fat and fibrotic tissue, pointing to an inability of the muscle to repair itself4. By contrast, healthy young skeletal muscle has a remarkable regenerative capacity, even after injury. Moiseeva et al. set out to investigate how the presence of senescent cells might underlie skeletal muscle’s diminishing ability to regenerate with age in mice.

The first challenge was to selectively isolate senescent cells from muscle tissue. The enzyme senescence-associated β-galactosidase (SA-β-gal) is highly active in senescent cells. The authors collected muscle tissue that had previously been damaged, and treated it with a fluorogenic substrate that fluoresces when cleaved by SA-β-gal. This enabled them to separate fluorescent senescent cells from other cells using a well-established approach called fluorescence-activated cell sorting. The group observed many more senescent cells in ageing tissue than in young tissue after injury. They also used their cell-labelling strategy to identify and study the positions of the cells in the injured tissue in vivo.

Tissue regeneration requires both stem cells and surrounding ‘niche’ cells, which can influence the behaviour of the stem cells. Moiseeva and colleagues examined gene expression and chromatin (the DNA–protein complex in which genetic material is packaged in the nucleus) in the senescent cell populations from young and old animals. They found that senescent cells — even those from young animals — make up part of the niche and have inflammation-promoting characteristics, which are associated with age-related declines in health (Fig. 1). The authors showed that several different cell types give rise to senescent cells, including skeletal muscle stem cells, myeloid cells and fibro-adipogenic cells, the last of which can promote inflammation, fat deposition and fibrosis in ageing animals5.

Figure 1

Figure 1 | Senescent cells inhibit recovery from injury. Moiseeva et al.2 have analysed populations of senescent cells in injured muscle from mice of various ages. a, They found that, regardless of age, injury leads to an increase in the number of senescent cells (with the increase much more pronounced in older animals, not shown). The cells produce factors that trigger inflammation of the tissue and lead to the formation of fibrotic (scar) tissue, preventing muscle regeneration. b, When the authors gave the animals drugs that kill senescent cells, they found improved muscle repair by stem cells.

The group’s discovery that senescent-cell numbers increased drastically after damage highlights a mechanism that might explain why some older people are more affected by ageing processes than others — if they have had an injury, more senescent cells might be present in their muscles. In line with this idea, geriatric mouse muscle that had been injured and so harboured senescent cells was less able to induce force than was uninjured geriatric tissue, even after the injury had repaired. However, the strength of the muscle was improved by giving the animals dasatinib and quercetin, drugs that can kill senescent cells. This shows that removal of senescent cells can improve muscle function.

Moiseeva et al. found that removal of senescent cells also improved muscle repair in younger animals. This finding was somewhat surprising, because senescence is not usually associated with younger animals (or people). The result therefore suggests that strategies to remove senescent cells might also help younger people to recover from muscle injury.

To explore the mechanism by which senescent cells block muscle regeneration, the group further profiled gene expression in the cells, and found a decrease in expression of genes related to the function of energy-producing organelles called mitochondria, and an increase in inflammatory genes, among other changes. In particular, interferon-stimulated genes (which are associated with inflammation) are upregulated in both ageing and senescence. Moreover, the authors found changes in collagen production, which have previously been linked to fibrosis6. Fibrosis interferes with regeneration by creating the equivalent of scar tissue, instead of competent normal tissue. In the case of skeletal muscle, fibrotic tissue forms instead of muscle fibres, thus impinging on muscle function.

Together, Moiseeva and colleagues’ findings indicate that senescent cells trigger inflammation and block regeneration throughout the animal’s life, and in particular seem to be responsible for many of the detrimental changes found in aged skeletal muscle. The changes in gene expression observed by the authors have also been shown to occur in the cells of aged tissue in general6, indicating that age-induced changes might be driven by senescent cells. It was not previously known that senescence might be the main driver of age-related gene changes. The work therefore gives fresh rationale to the strategy of seeking treatments that selectively remove senescent cells to combat age-related muscle weakness.