Study on the Role of SIRT2 in Stem Cell Aging and Chronic Inflammation

Aging is among the top known risk factors for most human diseases. Understanding the/nbiology of aging holds the promise to prevent or treat a wide range of seemingly/nunrelated diseases. Originally being viewed as a passive and irreversible accumulation/nof changes over time, aging is currently perceived as a progressive biological decline/nthat succumbs to genetic manipulations. Hallmarks of aging have been identified,/nincluding but not limited to, stem cell exhaustion, mitochondrial dysfunction, deregulated/nnutrient sensing, and genomic instability. However, the molecular mechanisms/ndetermining the aging process remain elusive. In particular, the cell/tissue specific/nresponses to aging-associated damages still await investigation. This knowledge is/npivotal to understand the molecular basis of the heterogeneous effects of aging on/ndiverse tissues. The aim of this dissertation work was to gain molecular insights into this/nknowledge by studying the two striking aspects of aging: stem cell dysfunction and/nchronic inflammation./nAdult stem cells maintain tissue homeostasis throughout life. It has been known for/ndecades that adult stem cell function declines with age, however, the exact mechanisms/ncontributing to this degeneration remain tentative. We found that SIRT2, a primarily/ncytosolic NAD+-dependent deacetylase, is required for hematopoietic stem cell (HSC)/nmaintenance at old age. Mechanistic studies demonstrated that SIRT2 exerts its role/nthrough modulating cell death processes in HSCs. SIRT2 expression is significantly/nreduced in old HSCs, which is consistent with increased cell death in HSCs during/naging. Enforced SIRT2 expression reverses the increased cell death observed in HSCs/nduring physiological aging. Further, we show that restoring SIRT2 expression can/nrejuvenate the functionality of old HSCs, suggesting the reversibility of the functional/ndecline in HSCs with age./nSIRT2 has been reported to suppress inflammation in multiple inflammation-inducing/nmouse models. Based on these findings, we investigated SIRT2’s role in chronic sterile/ninflammation associated with physiological aging. Chronic NLRP3 inflammasome/nactivation during aging has a causal role in developing pathological inflammation in/nsterile inflammatory diseases, such as atherosclerosis, Alzheimer’s disease,/nParkinson’s disease, obesity, diabetes, multiple sclerosis, and cancer. In light of this, we/nexplored whether SIRT2 suppresses aging-associated chronic inflammation through/nregulating the NLRP3 inflammasome activity. We found that SIRT2 specifically inhibits/nNLRP3 inflammasome in macrophages. NLRP3 inflammasome is activated in/nmacrophages with age, with a concomitant reduction in SIRT2 levels. Enforced SIRT2/nexpression in macrophages from old mice reverses aging-associated NLRP3/ninflammasome activation, suggesting a potential reversible mechanism for the agingassociated/ninflammation phenotype./nOur studies demonstrate that down-regulation of SIRT2 levels plays significant roles in/ndifferent cells and tissues during aging. In HSCs, SIRT2 suppresses the activation of/ncell death processes and preserves HSC regenerative capacity, while in macrophages,/nSIRT2 mediated NLRP3 inhibition prevents the development of chronic inflammation./nThese results not only broaden the physiological relevance of the cytosolic NAD+/nprotein deacetylase SIRT2 to include stem cell homeostasis, but also exemplify the/nheterogeneity in tissue responses to aging-associated down-regulation of the SIRT2/nprotein expression. Further, from the therapeutic standpoints, these findings also open/nnovel avenues to explore the potential reversibility of both stem cell aging and systemic/nlow-grade inflammation associated with aging.

Advisor: Chen, Danica