Ever more cells in our tissues become senescent with age, entering a program of behavior that appears to be - at least partially - an adaptation to suppress cancer. A senescent cell leaves the cell cycle, stops dividing, and starts to emit signaling molecules that harm surrounding tissues and encourage other cells to become senescent. Some senescent cells destroy themselves or are killed by the immune system, but their numbers still grow greatly in later life. This degrades health and contributes to the pathology of age-related diseases.
Senescence is distinct from quiescence, the other state in which a cell stops dividing: quiescent cells offer no harm and are generally well-behaved. Many populations of stem cells, for example, spend most of their time in a quiescent state, awaiting the call to action or periodic revival to maintain tissues by generating replacement cells. In recent work, researchers suggest that senescence is a reaction to simultaneous signals telling a cell to replicate and not replicate: the need to maintain tissues (go forth and multiply) combined with high levels of cellular damage (stay put because it is too risky to act), for example.
An intriguing interpretation of cell senescence postulates that this unique phenotype emerges when a cell integrates two types of signals: one that reads for growth and one that imposes a block in the replicative cycle. For example, DNA damaging agents do not induce senescence in quiescent cells; however, they do so if the presence of persistent DNA damage and cell cycle arrest is coupled with growth promoting stimuli. Under these conditions, cells switch on the senescence program and express markers related to both cell cycle block and growth stimulation.
Building on this vision, below you'll find another look at the triggering of senescence in aged stem cells - muscle stem cells this time, important to the progression of sarcopenia, the loss of muscle mass and strength with aging. One of the possible approaches to senescent cells, and probably the easiest, is to remove them using some form of targeted cell destruction technology of the sort under development in the cancer research community. Another approach is to try to reverse senescence: if it is largely a reaction to damage, it might be the case that repair of cellular damage in the SENS model of rejuvenation biotechnology will result in reduced levels of cellular senescence. Alternatively scientists could aim to brute force the process by overriding signaling processes without addressing the underlying causes of signaling changes, which is the approach taken in most modern medical research, and that offered here.
Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities.
In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment.
p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16INK4a is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.
It is promising to see yet another study demonstrating that old stem cells retain the potential to do their jobs. The p16 gene is clearly going to be an increasingly important research topic in the years ahead based on its close connection with cellular senescence.