As a companion piece to another recently published open access paper, noted earlier this week, today’s review paper considers the therapeutic upregulation of autophagy as a possible approach to reduce the deleterious impact of aging on muscle regeneration. Autophagy is the name given to a collection of cellular housekeeping processes responsible for ensuring that excess and broken cellular components are transported to a lysosome for recycling. Lysosomes are membrane-bound vesicles packed with enzymes capable of breaking down near all structures and molecular waste they are likely to encounter. The remnant molecules are released back into the broader cell as raw materials.

Autophagy is known to decline with age. Many of the approaches shown to slow aging in short-lived laboratory species either involve increased autophagy, or, as is the case for calorie restriction, appear to depend on increased autophagy for the beneficial effects on health and life span. Increased autophagy is a feature of many forms of cellular stress response: heat, cold, lack of nutrients, oxidative damage, and so forth. Mild or short-lived stress or damage can provoke a reaction that lasts for a while and produces an overall gain in cell function. Since autophagy removes damaged components, it limits the opportunity for damage to spread and produce downstream effects. When that is happening in every cell in the body on a regular basis, the result is a longer life span.

Unfortunately, what we know of the effects of calorie restriction in mice and humans tells us that stress responses such as upregulated autophagy have a much larger effect on life span in short-lived species than they do in long-lived species such as our own. Calorie restriction can increase maximum mouse life span by 40%. In humans an effect size of more than five years would be surprising, given that any reliable gain much larger than that would have been discovered in antiquity and very well explored by now. Which is not to say that calorie restriction is worthless: it produces a larger reliable gain in long term health – for basically healthy people – than any readily available, well understood medical technology. Given the advent of senolytics as a rejuvenation therapy, that statement probably won’t remain true for very much longer, but it is worth considering.

Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function.

The pharmacological induction of autophagy represents a promising strategy to improve stress resistance and regeneration of skeletal muscle. Spermidine and rapamycin are two examples of drugs that have been studied for their autophagy-inducing effects and lifespan extension in rodent models. While rapamycin acts directly on mTOR, spermidine’s polyamine effects on histone acetylation status upregulates various autophagy-related transcripts and suppresses necrosis. The positive benefits of spermidine in muscle tissues of mice and rats have been shown by mitigating age-related muscular atrophy as well as functional myopathies that originate from autophagy failure.

Spermidine also modulates macrophage polarization in mice towards reduced inflammation, though some evidence suggests the autophagy inducing effects of rapamycin more directly target T lymphocytes. Taken together, these agents act as “caloric restriction mimetics” to induce autophagy and contribute to improvements in lifespan of mice. Specifically, the effects of autophagy induction show promise as it related to therapies targeting muscle stem cell myogenic capacity.

Muscle stem cells and monocytes/macrophages are essential for skeletal muscle homeostasis and regeneration. A common theme among these cell populations is the idea that autophagy is a key process that is altered in aged cells leading to functional decline. Autophagy is no longer an emerging regulator of cellular function but has consistently been shown to play a central and important role, especially in the context of aging. Stem cells, in particular, show dysfunctional autophagy during initial stages of activation while caloric restriction and physical activity allow a sensitization to autophagy with beneficial outcomes in cellular activation and function. The exact role for autophagy in muscle regeneration will be complex considering the temporal nature and diverse cell types contributing to the regenerative program. However, global induction of autophagy appears beneficial to the regenerative capacity in the aged muscle. Continuing to uncover the molecular events responsible for age-related perturbations in these pathways is critical for exposing pharmaceutical targets to combat the aging process and improve tissue regeneration in aged individuals.

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