Cellular senescence is a hallmark of the aging process and contributes to chronic disease vulnerability.
Although senescence acts acutely as a tumor suppressor mechanism, chronically it also contributes to
inflammation in aged tissue through the senescence-associated secretory phenotype (SASP). Hence, removal
of senescent cells in vivo improves healthspan and lifespan, and rescues pathology associated with a plethora
of phenotypes and diseases of aging. However, pharmacological “senolytic” approaches tend to have toxic
side effects, likely limiting the utility of senolytics as tools to promote healthy aging. As proof-of-concept for an
alternative approach, suppression of SASP in vivo reduces chronic liver inflammation and delays onset of
Recently, we have shown that SASP is dependent on expulsion of cytosolic chromatin fragments (CCF) from
the nucleus into the cytoplasm of senescent cells. Senescent cells harbor dysfunctional mitochondria, as
reflected by decreased membrane potential, elevated ROS production, decreased mitophagic turnover, and
altered intermediary metabolism. We have recently linked dysfunctional mitochondria in senescent cells to
CCF production, and hence SASP, through a retrograde mitonuclear signaling pathway. This pathway
involves mitochondrial ROS-mediated activation of the kinase JNK1/2, which is required for CCF formation,
and the DNA repair protein 53BP1, which suppresses CCF formation. However, the mechanism linking
JNK1/2 to 53BP1 is unknown.
Extending these findings, studies in non-vertebrate organisms also suggest that mitochondria-nucleus
retrograde signaling pathways can modify aging and longevity, altogether suggesting that identification and
targeting of these pathways has therapeutic potential in the treatment of age-associated diseases. However,
these pathways are poorly understood in mammalian systems.
I hypothesize that mitonuclear signaling in senescent cells modulates the senescent cell phenotype and hence
senescence-associated human disease. This proposal has two Aims in the mentored K99 phase, to: 1)
Determine the mechanism by which JNK1/2 regulates 53BP1 to induce CCF formation; 2) Investigate
the 53BP1-independent role of JNK1/2 senescent cells; and an additional Aim in the independent R00
phase, to 3) Investigate the role of mitochondria-mediated suppression of ATF4 and crosstalk between
other stress responses in senescent cells. Elucidation of these mitonuclear signaling pathways in
mammalian cells is of broad general interest to all biologists but can also identify therapeutic targets for
reduction of SASP. This approach can uncover alternatives to senolytic drugs for treatment of age-associated
disease and promote healthy aging.