Year: 2017
Type: dissertation
Abstract: Aging is among the top known risk factors for most human diseases. Understanding thebiology of aging holds the promise to prevent or treat a wide range of seeminglyunrelated diseases. Originally being viewed as a passive and irreversible accumulationof changes over time, aging is currently perceived as a progressive biological declinethat succumbs to genetic manipulations. Hallmarks of aging have been identified,including but not limited to, stem cell exhaustion, mitochondrial dysfunction, deregulatednutrient sensing, and genomic instability. However, the molecular mechanismsdetermining the aging process remain elusive. In particular, the cell/tissue specificresponses to aging-associated damages still await investigation. This knowledge ispivotal to understand the molecular basis of the heterogeneous effects of aging ondiverse tissues. The aim of this dissertation work was to gain molecular insights into thisknowledge by studying the two striking aspects of aging: stem cell dysfunction andchronic inflammation.Adult stem cells maintain tissue homeostasis throughout life. It has been known fordecades that adult stem cell function declines with age, however, the exact mechanismscontributing to this degeneration remain tentative. We found that SIRT2, a primarilycytosolic NAD+-dependent deacetylase, is required for hematopoietic stem cell (HSC)maintenance at old age. Mechanistic studies demonstrated that SIRT2 exerts its rolethrough modulating cell death processes in HSCs. SIRT2 expression is significantlyreduced in old HSCs, which is consistent with increased cell death in HSCs duringaging. Enforced SIRT2 expression reverses the increased cell death observed in HSCsduring physiological aging. Further, we show that restoring SIRT2 expression canrejuvenate the functionality of old HSCs, suggesting the reversibility of the functionaldecline in HSCs with age.SIRT2 has been reported to suppress inflammation in multiple inflammation-inducingmouse models. Based on these findings, we investigated SIRT2’s role in chronic sterileinflammation associated with physiological aging. Chronic NLRP3 inflammasomeactivation during aging has a causal role in developing pathological inflammation insterile inflammatory diseases, such as atherosclerosis, Alzheimer’s disease,Parkinson’s disease, obesity, diabetes, multiple sclerosis, and cancer. In light of this, weexplored whether SIRT2 suppresses aging-associated chronic inflammation throughregulating the NLRP3 inflammasome activity. We found that SIRT2 specifically inhibitsNLRP3 inflammasome in macrophages. NLRP3 inflammasome is activated inmacrophages with age, with a concomitant reduction in SIRT2 levels. Enforced SIRT2expression in macrophages from old mice reverses aging-associated NLRP3inflammasome activation, suggesting a potential reversible mechanism for the agingassociatedinflammation phenotype.Our studies demonstrate that down-regulation of SIRT2 levels plays significant roles indifferent cells and tissues during aging. In HSCs, SIRT2 suppresses the activation ofcell death processes and preserves HSC regenerative capacity, while in macrophages,SIRT2 mediated NLRP3 inhibition prevents the development of chronic inflammation.These results not only broaden the physiological relevance of the cytosolic NAD+protein deacetylase SIRT2 to include stem cell homeostasis, but also exemplify theheterogeneity in tissue responses to aging-associated down-regulation of the SIRT2protein expression. Further, from the therapeutic standpoints, these findings also opennovel avenues to explore the potential reversibility of both stem cell aging and systemiclow-grade inflammation associated with aging.
Author: Hanzhi Luo
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2953140103