Dr. Pura Muñoz-Cánoves’ Group recently published in Nature one possible explanation for the loss of tissue regenerative capacity with aging. In tissues with little turnover, stem cells (which repair tissues and organs) remain in a dormant, quiescent state. The stem cells of skeletal muscle (also called satellite cells) were thought to be quiescent throughout life, only activating in response to damage or stress. Dr. Muñoz-Cánoves and colleagues hypothesized that satellite cells would progressively accumulate intracellular toxic debris over their lifespan, and would therefore need an efficient ‘clean-up’ system to maintain protein homeostasis (proteostasis). These ideas led them to investigate the possible role of autophagy, a system used by cells to degrade damaged proteins and organelles in vesicular structures called lysosomes. Recent evidence shows that, at advanced, geriatric life stages, satellite cells lose quiescence and enter an irreversible state of proliferative block called senescence, leading to defective muscle regeneration. Using autophagy-reporting mice, these researchers found that adult satellite cells, despite their dormant state, maintain a basal autophagic activity. In old age, however, this activity is lost, causing accumulation of damaged mitochondria. Mitochondria are the essential organelles of energy production, and the accumulated dysfunctional mitochondria generate high levels of reactive oxygen species (ROS), causing further damage to proteins and DNA. This loss of proteostasis provokes senescence entry and impairs satellite cell functions. By reactivating autophagy or inhibiting ROS production in aged satellite cells, they were able to prevent senescence, restore stem-cell self-renewal, and reboot the capacity to form new muscle fibres. The identification of autophagy as an obligatory activity for maintaining stem-cell fitness, despite these cells’ low metabolic activity, not only advances the understanding of stem-cell biology, but also suggests research avenues into potential regenerative medicine applications.
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