SQSTM1 is also known as P62. The protein expressed by this gene assists in the selection and transport of materials to be recycled via autophagy, an important stress response mechanism. Once a protein or structure has been decorated with a ubiquitin molecule, SQSTM1 binds to that protein or structure as a part of the complicated process of shuttling it to a lysosome where it can be broken down. Thus too little SQSTM1 impairs autophagy and more SQSTM1 can enable more efficient autophagy. This can influence the pace of aging, as illustrated by the numerous interventions that both slow aging and which feature enhanced autophagy. In at least a few such cases, such as for calorie restriction, autophagy has been shown to be necessary for slowed aging to occur. Unfortunately, this class of approaches to the treatment of aging has much larger effects on life span in short-lived species than it does in long-lived species such as our own.
In today's open access paper researchers review some of the biochemistry immediately surrounding SQSTM1 and autophagy, with a particular focus on cellular senescence and skin aging. Senescent cells accumulate in aging tissue, generating inflammatory signaling that is disruptive to tissue structure and function. More efficient autophagy appears to help resist entry to the senescent state, and can thus in principle reduce the burden of senescent cells in aged tissue to some degree over time, assuming the immune system is competent enough to catch up on its task of destroying senescent cells. Clinical trials in humans to conclusive prove this point and quantify the size of the benefits remains an aspiration, even for very well established drugs like rapamycin.
SQSTM1/p62 Orchestrates Skin Aging via USP7 Degradation
USP7 regulates intracellular protein homeostasis through selective substrate degradation. It plays a crucial role in cell cycle control, senescence, and cancer by interacting with diverse target protein. Sequestosome1 (SQSTM1 or p62), hereafter p62, an autophagy receptor, has been associated with aging and age-related diseases, including neurodegeneration, infections, cancer, and oxidative stress-related conditions. p62 deficiency is associated with a shorter lifespan, elevated oxidative stress, synaptic deficiencies, and memory impairment. By interacting with GATA4, p62 promotes selective autophagic degradation, inhibiting cellular senescence.
In the dermis, fibroblasts regulate collagen expression and maintain skin integrity. However, senescent fibroblasts contribute to dermal thinning, increased wrinkle formation, and skin sagging. Keratinocytes also play a pivotal role in shaping the senescent skin microenvironment, including the maintenance of the dermal-epidermal junction and the secretion of senescence-associated secretory phenotype (SASP) factors. Notably, senescent keratinocytes exhibit enrichment of SASP components, including proinflammatory cytokines and proteases. The consequent decline in cellular and tissue regenerative potential is implicated in the progression of skin aging. However, the precise mechanisms through which p62 regulates keratinocytes in skin aging are unknown.
In this study, we investigate the function of p62 and potential mechanisms in skin aging and cellular senescence. We identified p62 as a negative regulator in skin aging and senescent keratinocytes. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of USP7 during senescence induction by orchestrating its degradation through specific binding interactions. Importantly, this study provides the first time, to our knowledge, that p62 plays a critical role and regulates specific mechanisms in skin aging and cellular senescence.
View the full article at FightAging
