# Sphingolipid Metabolism and Signaling in the Regulation of Senescence and Aging

> **NIH NIH R56** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $369,786

## Abstract

SUMMARY
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).

## Key facts

- **NIH application ID:** 10253130
- **Project number:** 1R56AG069769-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Besim Ogretmen
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,786
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10253130

## Citation

> US National Institutes of Health, RePORTER application 10253130, Sphingolipid Metabolism and Signaling in the Regulation of Senescence and Aging (1R56AG069769-01). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10253130. Licensed CC0.

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