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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2017)

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.

    Cover page: Study on the Role of SIRT2 in Stem Cell Aging and Chronic Inflammation
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2017)
    The simplicity and effectiveness of calorie restriction (CR) in lifespan and healthspan extension have fascinated generations searching for the Fountain of Youth. CR reduces levels of oxidative stress and damage, which have been postulated in the free radical theory of aging as a major cause of aging and diseases of aging. This reduction has long been viewed as a result of passive slowing of metabolism. Recent advances in nutrient sensing have provided molecular insights into the oxidative stress response and suggest that CR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Physiological studies have provided strong support for oxidative stress in the development of aging-associated conditions and diseases but have also revealed the surprising requirement for oxidative stress to support normal physiological functions and, in some contexts, even slow aging and prevent the progression of cancer. Deciphering the molecular mechanisms and physiological implications of the oxidative stress response during CR will increase our understanding of the basic biology of aging and pave the way for the design of CR mimetics to improve healthspan.
      Cover page: Nutrient Sensing and the Oxidative Stress Response
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2015)
      Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPR(mt)), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFS(mt)), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPR(mt)-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.
        Cover page: A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2019)
        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.
          Cover page: Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2020)
          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.
            Cover page: An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance
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