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Stem cell aging contributes to aging-associated tissue degeneration and dysfunction. Recent studies reveal a mitochondrial metabolic checkpoint that regulates stem cell quiescence and maintenance, and dysregulation of the checkpoint leads to functional deterioration of aged stem cells. Here, we present the evidence supporting the mitochondrial metabolic checkpoint regulating stem cell aging and demonstrating the feasibility to target this checkpoint to reverse stem cell aging. We discuss the mechanisms by which mitochondrial stress leads to stem cell deterioration. We speculate the therapeutic potential of targeting the mitochondrial metabolic checkpoint for rejuvenating aged stem cells and improving aging tissue functions.

The free radical theory of aging was first proposed by Harman in the 1950s with the idea that oxidative damage accumulates with age and contributes to functional deteriorations during aging. Caloric restriction (CR) has been shown to be one of the most effective approaches to extend life span and health span. Recent advances in nutrient sensing have identified molecular regulators responsible for CR-mediated oxidative stress defense and underscore their importance in preserving stem cell maintenance and tissue integrity during aging. Deciphering molecular mechanisms of the oxidative stress response during CR will enhance our knowledge toward the biology of aging and provide insights into developing activators targeting the nutrient-sensing pathways to extend health span and life span.

Aging-associated defects in hematopoietic stem cells (HSCs) can manifest in their progeny, leading to aberrant activation of the NLRP3 inflammasome in macrophages and affecting distant tissues and organismal health span. Whether the NLRP3 inflammasome is aberrantly activated in HSCs during physiological aging is unknown. We show here that SIRT2, a cytosolic NAD+-dependent deacetylase, is required for HSC maintenance and regenerative capacity at an old age by repressing the activation of the NLRP3 inflammasome in HSCs cell autonomously. With age, reduced SIRT2 expression and increased mitochondrial stress lead to aberrant activation of the NLRP3 inflammasome in HSCs. SIRT2 overexpression, NLRP3 inactivation, or caspase 1 inactivation improves the maintenance and regenerative capacity of aged HSCs. These results suggest that mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome is a reversible driver of the functional decline of HSC aging and highlight the importance of inflammatory signaling in regulating HSC aging., Cell Reports, 26 (4), ISSN:2666-3864, ISSN:2211-1247

It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD(+)-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models, and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.