BCL-2 and related proteins are major regulators of apoptosis that have emerged as promising targets for the elimination senescent cells (or ‘senolysis’) to improve age-related diseases and promote healthy ageing. However, seminal observations and recent findings shed light on non-apoptotic roles of BCL-2 proteins in the regulation of cellular senescence.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021).
Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
Wang, L. et al. Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 34, 75–89 (2022).
Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016).
Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20, 175–193 (2019).
O’Reilly, L. A., Huang, D. C. & Strasser, A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J. 15, 6979–6990 (1996).
Linette, G. P., Li, Y., Roth, K. & Korsmeyer, S. J. Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation. Proc. Natl. Acad. Sci. USA 93, 9545–9552 (1996).
Brady, H. J., Gil-Gomez, G., Kirberg, J. & Berns, A. J. Bax alpha perturbs T cell development and affects cell cycle entry of T cells. EMBO J. 15, 6991–7001 (1996).
Ichim, G. et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 57, 860–872 (2015).
Passos, J. et al. Sub-lethal apoptotic stress enables mtDNA release during senescence and drives the SASP. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-1247316/v1 (2022).
We thank B. Manship for editing the article. We sincerely apologize to the many authors whom we could not cite due to space limitations. Our work was supported by the Fondation ARC, the Ligue contre le Cancer and the INCA.
The authors declare no competing interests.
Peer review information
Nature Reviews Molecular Cell Biology thanks Ana García-Sáez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Rights and permissions
About this article
Cite this article
Martin, N., Popgeorgiev, N., Ichim, G. et al. BCL-2 proteins in senescence: beyond a simple target for senolysis?. Nat Rev Mol Cell Biol (2023). https://doi.org/10.1038/s41580-023-00594-y