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Autophagy Key to Restoring Function in Old Muscle Stem Cells

A most interesting paper surfaced today, after spending more than a year in the peer review process. The current press coverage is in Spanish only, but we all have access to automated translation these days. The authors of the paper report that the muscle stem cell population known as satellite cells, responsible for regeneration and tissue maintenance, relies upon autophagy to evade the onset of cellular senescence. Unfortunately autophagy fails with age, a decline that is linked to the accumulation of metabolic waste in long-lived cells, but probably has other less direct contributing factors as well. When stem cells fall into senescence, their activity and effectiveness declines. The researchers demonstrated that restoring youthful levels of autophagy in old satellite cell populations can restore them from senescence and return their regenerative capabilities. This has its analogies in earlier work, such as the approach taken to restore function in aged liver tissue back in 2008.

Autophagy is an collection of cellular maintenance processes, focused on clearing out waste and recycling damaged components. Greater autophagy taking place in tissue should mean fewer damaged and disarrayed cells at any given moment in time, which in turn should translate to a longer-lasting organism. The paper linked below is one of the more compelling of recent arguments for putting more effort into treatments based on artificially increased levels of autophagy. This has been a topic in the research community for some time, as many of the methods known to modestly slow aging in laboratory species are associated with increased levels of autophagy. It is a vital component in hormesis, wherein causing a little damage leads to a lasting increase in autophagy and a net gain.

Stem cells spend much of their time in a state of quiescence, only springing into action when called upon. This helps to preserve them for the long term. In older tissues with greater levels of molecular damage, ever more stem cells slip from quiescence into an irreversible senescent state. These senescent cells are no longer capable of generating new cells, and start to secrete all sorts of harmful signal molecules. Cellular senescence is thought to be a response to damage or a toxic environment, so you can probably see how this might be expected to tie into repair processes such as autophagy. There is some debate over the degree to which cellular senescence is irreversible in the normal course of events inside a living organism. When reductions in senescence are observed in a cell population as a result of changing circumstances or a treatment, it may simply be that the relative number of senescent cells falls without any such cell returning to a non-senescent status. Cell populations are dynamic, after all.

Scientists discover how to keep the body young despite age (Spanish)

Muscles have a cleaning system that eliminates waste and preventing degenerate over the years, as scientists have discovered. When this cleaning system stops working properly, the muscles go into senescence. Then, stem cells lose the ability to regenerate tissue and muscle is weakened. It's something that happens gradually from the fifth decade of life and that in elderly people forces them into frailty. But when the cleaning system is restored, as have researchers with drugs, muscle tissue can regenerate again and retrieves the lost vigor. So far the experiments have been performed in mice and in human cells in the laboratory.

The cleaning system, technically called autophagy, removes components of cells that have stopping functioning properly and become toxic. These components range from individual molecules (free radicals or damaged proteins) to whole organelles (such as mitochondria or ribosomes). Since all organs and tissues of the human body depend on autophagy, researchers believe that the same system could be key to slow aging in other organs, and it could be useful to increase their regenerative capacity and rejuvenate. "I think it must be so because every house has to be cleaned, and autophagy is a very fundamental cleaning mechanism in living organisms, but we have not proven that our research is not limited to muscle tissue."

In muscle, autophagy has been shown to maintain the ability of stem cells to regenerate tissue. And when autophagy is no longer efficient and cells begin to accumulate waste, stem cells enter senescence and lose their regenerative capacity. "We were surprised to discover this. When you stop to think about it, it makes sense, because the stem cells need to break free of waste accumulate every day to work properly." But despite intensive research in the last decade on the biology of aging, "this is the first time a relationship between aging and declining autophagy in mammalian tissue is observed. Although senescence due to aging is often seen as an inevitable and irremediable process, we demonstrate that the internal clock of aging stem cells can be manipulated with drugs."

Autophagy maintains stemness by preventing senescence

During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
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