Lipid metabolism and signaling play key roles in the regulation of senescence and longevity. The bioactive sphingolipid ceramide induces senescence, and that inhibition of ceramide synthesis results in increased life span. One of the down-stream targets of anti-proliferative ceramide is telomerase, which is transcriptionally silenced by ceramide, resulting in senescence in various mammalian cells. Ceramide can be metabolized to generate pro-survival sphingosine 1-phosphate (S1P) by sphingosine kinases 1 or 2 (SphK1 or SphK2). While SphK1-generated S1P plays important roles in G protein coupled receptor (GPCR) signaling in the plasma membrane, SphK2/S1P is localized mainly to nuclear membrane. Our preliminary data suggest that SphK2- generated S1P binds telomerase reverse transcriptase (TERT) protein, stabilizing telomerase, protecting various human and murine cell types, including fibroblasts and lung epithelial cells, from telomere damage and subsequently delaying senescence. Reciprocally, pharmacologic inhibition or genetic deletion of SphK2, but not SphK1, results in rapid TERT ubiquitination/degradation, accelerating telomere damage, and inducing senescence in fibroblasts in culture and in testes or skin tissues of SphK2-/- mice in vivo. However, how SphK2- generated S1P binds and controls TERT stability, and how inhibition of SphK2/S1P metabolism results in accelerated aging through induction of senescence in response to telomerase instability and telomere damage signaling remain unknown, which will be answered in this application. Thus, this application is designed to test a novel hypothesis that sphingolipid signaling by SphK2/S1P in nuclear membranes regulate senescence and aging by controlling telomerase and telomere damage. This hypothesis will be tested in the following Specific Aims:
Aim 1) Determine the mechanism whereby SphK2-generated S1P regulates telomerase stability and senescence.
Aim 2) Define how telomere damage induced by inhibition of the SphK2/S1P-hTERT complex mediates senescence.
Aim 3) Identify how inducing SphK2/S1P metabolism and signaling prevents telomere damage-induced senescence and aging. Because of our strong expertise in sphingolipid signaling, we are ideally positioned to develop mechanism-based interventions to control telomerase/telomere-damage/senescence and increase life and/or health span, which have important implications in aging-associated diseases such as cancer and Alzheimer?s disease (AD).
