SQSTM1 Overexpression Extends Life in Nematode Worms

Macroautophagy is a cellular recycling process in which unwanted proteins and cell structures are engulfed by an autophagosome that is then transported to a lysosome, where its contents are broken down. Greater autophagy is a feature of many of the approaches shown to slow aging in laboratory species. In principle this should lead to better cell function and less downstream damage resulting from uncleared issues in cells. Many different approaches to the upregulation of autophagy have been demonstrated in the laboratory, but this class of therapy has yet to make the leap to the clinic. Arguably mTOR inhibition is the closest to realization, but more targeted methods of increasing autophagy are still largely stuck in the laboratory stage of research and development.

As an example of the type, researchers here investigate upregulation of autophagy via increased production of one portion of the protein machinery necessary for the operation of autophagy. This sort of approach has worked well for other cellular maintenance structures, such as the proteasome. The protein SQSTM1, also known as p62, assists in selecting materials to be recycled. Ubiquitination, the decoration of a protein with ubiquitin, is one of the ways in which a cell determines which proteins and structures are targeted for recycling. SQSTM1 binds to ubiquinated proteins in order to shuttle them into an autophagosome. As demonstrated in this research, greater production of SQSTM1 leads to more efficient autophagy, and thus a slowing of degenerative aging in short-lived nematode worms.

Given what is known of calorie restriction in various species, an intervention that functions to improve health and extend life largely via increased autophagy, we should take this research as interesting but not necessarily all that relevant to human life spans. Calorie restriction greatly extends life span in short-lived species, but adds at most a few years to life span in long-lived species such as our own. This pattern of lesser life extension for species with longer life spans is true of all of the stress response mechanisms that influence aging. Nonetheless, calorie restriction does improve human health significantly. Thus we should temper our expectations regarding therapies based on upregulation of autophagy: some degree of improved health is the expected outcome, not meaningfully greater longevity.

The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy

Macroautophagy (hereafter called autophagy) facilitates degradation and recycling of cytosolic components, referred to as cargo, in response to nutrient deprivation or other stressors. Autophagy is initiated by the nucleation of a double membrane, which forms the phagophore. As the phagophore expands, it begins to sequester cytosolic cargo into the growing vesicle. Upon completion, the autophagosome or amphisome (formed by fusion with vesicles from the endolysosomal compartments) then fuse with acidic lysosomes, resulting in the degradation of the sequestered content by hydrolases.

Autophagy is essential for survival, development, and organismal homeostasis. It occurs at low levels under basal conditions, whereas developmental stimuli or cellular stress, including starvation and heat shock, can induce autophagy. Furthermore, autophagy can protect against pathologies, including neurodegeneration and aging. The regulation of autophagy with age is incompletely understood, but several lines of evidence suggest that autophagy declines with age. Conversely, autophagy genes are essential for lifespan extension in distinct longevity paradigms in S. cerevisiae, C. elegans, and Drosophila. While these observations demonstrate a link between autophagy and aging, it remains unclear how the autophagy process affects longevity and healthspan.

Autophagy was originally described as a 'bulk' turnover process, in which cytosolic components are indiscriminately recycled to provide amino acids and other building blocks during nutrient deprivation and cellular stress. Emerging evidence indicates that selective types of autophagy degrade specific and possibly damaged cytosolic components in a tightly regulated manner. During selective autophagy, autophagosomes recruit specific types of cargo, including mitochondria and protein aggregates, through the action of autophagy receptors that connect the autophagosome to the cargo. The selective autophagic degradation of ubiquitinated protein aggregates, termed aggrephagy, can be facilitated by autophagy receptor p62/SQSTM1 (hereafter referred to as p62).

The degradation of ubiquitinated proteins can occur via autophagy as well as the ubiquitin-proteasome system (UPS), and p62 has been implicated in both processes; i.e., as a selective autophagy receptor, and through the delivery of ubiquitinated proteins for degradation to the proteasome. Consistent with a key role in age-related disease, mice deficient in p62 have reduced lifespan, increased oxidative stress, synaptic deficiencies, and memory impairment. The expression levels of p62 have been shown to decline with age in mice, and reduced expression of p62 correlates with age-related neurodegenerative diseases in humans. Notably, we recently reported that sqst-1 mRNA levels are markedly increased upon heat stress in C. elegans, prompting the hypothesis that SQST-1 may play a role in the heat-shock response, in which heat-shock proteins and molecular chaperones are rapidly and transiently induced to ameliorate the deleterious effects of heat stress.

Since emerging evidence suggests that the degradation of specific cargos by selective autophagy is important for maintaining health, we investigated the role of SQST-1 in hormetic heat shock, lifespan, and proteostasis. Here we demonstrate that sqst-1 is required for autophagy induction as well as organismal benefits conferred by a hormetic heat shock. Furthermore, we show that overexpression of SQST-1 is sufficient to increase longevity in C. elegans. SQST-1 overexpression leads to tissue-specific induction of autophagy. These observations illustrate that overexpression of a selective autophagy receptor is sufficient to induce autophagy and enhance longevity and proteostasis. As p62 plays an important role in many age-related diseases, our findings highlight potential therapeutic opportunities in inducing p62-mediated selective autophagy.


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