Researchers here report on a novel approach to slow aging and extend life in mice by interfering in the activity of a protein involved in the regulation of metabolism. The researchers find that SAPS3 expression increases with age, and deletion of this gene slows metabolic aging. SAPS3 is a component of a protein complex that reduces levels of AMPK. Upregulation of AMPK is known to slow aging, and here that is achieved by disabling the SAPS3-related process that acts to reduce AMPK levels. The size of the effect on life span in mice is modest, as one might expect given past work on AMPK and aging. This illustrates the point that biochemistry is complex, and for any given target there are many different ways (upstream and downstream in networks of protein interactions) in which one can intervene to achieve a given result.
Aging is characterized by disruptions in metabolic homeostasis, yet the mechanisms that regulate these metabolic changes remain poorly understood. We show that the serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3, SAPS3, is a critical regulator of metabolism during aging. SAPS3 deletion significantly extends lifespan in mice and counteracts age-related impairments in metabolic health. SAPS3 deficiency improves the effects of aging on the affective behaviors, cognition, and motor functions in aged mice.
We find that SAPS3 expression is increased during aging to inhibit adenosine monophosphate-activated kinase (AMPK) activity. Deletion of SAPS3 leads to AMPK activation and reverses cellular senescence and aging-induced metabolic alterations. Using in vivo U-13C6-D-glucose tracing and metabolomic analysis, we find that SAPS3 deficiency restores metabolic homeostasis with increased glycolysis, tricarboxylic acid (TCA) cycle, and decreased fatty acid synthesis in aged mice. These findings highlight a critical role of the SAPS3/PP6 phosphatase complex in aging and suggest that strategies targeting SAPS3 may promote longevity and healthy aging.
Link: https://doi.org/10.1126/sciadv.adt3879
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