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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

biology of aging holds the promise to prevent or treat a wide range of seemingly

unrelated diseases. Originally being viewed as a passive and irreversible accumulation

of changes over time, aging is currently perceived as a progressive biological decline

that succumbs to genetic manipulations. Hallmarks of aging have been identified,

including but not limited to, stem cell exhaustion, mitochondrial dysfunction, deregulated

nutrient sensing, and genomic instability. However, the molecular mechanisms

determining the aging process remain elusive. In particular, the cell/tissue specific

responses to aging-associated damages still await investigation. This knowledge is

pivotal to understand the molecular basis of the heterogeneous effects of aging on

diverse tissues. The aim of this dissertation work was to gain molecular insights into this

knowledge by studying the two striking aspects of aging: stem cell dysfunction and

chronic inflammation.

Adult stem cells maintain tissue homeostasis throughout life. It has been known for

decades that adult stem cell function declines with age, however, the exact mechanisms

contributing to this degeneration remain tentative. We found that SIRT2, a primarily

cytosolic NAD+-dependent deacetylase, is required for hematopoietic stem cell (HSC)

maintenance at old age. Mechanistic studies demonstrated that SIRT2 exerts its role

through modulating cell death processes in HSCs. SIRT2 expression is significantly

reduced in old HSCs, which is consistent with increased cell death in HSCs during

aging. Enforced SIRT2 expression reverses the increased cell death observed in HSCs

during physiological aging. Further, we show that restoring SIRT2 expression can

rejuvenate the functionality of old HSCs, suggesting the reversibility of the functional

decline in HSCs with age.

SIRT2 has been reported to suppress inflammation in multiple inflammation-inducing

mouse models. Based on these findings, we investigated SIRT2’s role in chronic sterile

inflammation associated with physiological aging. Chronic NLRP3 inflammasome

activation during aging has a causal role in developing pathological inflammation in

sterile inflammatory diseases, such as atherosclerosis, Alzheimer’s disease,

Parkinson’s disease, obesity, diabetes, multiple sclerosis, and cancer. In light of this, we

explored whether SIRT2 suppresses aging-associated chronic inflammation through

regulating the NLRP3 inflammasome activity. We found that SIRT2 specifically inhibits

NLRP3 inflammasome in macrophages. NLRP3 inflammasome is activated in

macrophages with age, with a concomitant reduction in SIRT2 levels. Enforced SIRT2

expression in macrophages from old mice reverses aging-associated NLRP3

inflammasome activation, suggesting a potential reversible mechanism for the agingassociated

inflammation phenotype.

Our studies demonstrate that down-regulation of SIRT2 levels plays significant roles in

different cells and tissues during aging. In HSCs, SIRT2 suppresses the activation of

cell 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 the

heterogeneity in tissue responses to aging-associated down-regulation of the SIRT2

protein expression. Further, from the therapeutic standpoints, these findings also open

novel avenues to explore the potential reversibility of both stem cell aging and systemic

low-grade inflammation associated with aging.

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