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BCL-xL as a Longevity Gene


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Posted 01 June 2020 - 10:22 AM


BCL-xL is a mitochondrial protein that acts to suppress the programmed cell death response of apoptosis, and is overexpressed in some cancers, as well as in senescent cells. Thus small molecules that bind to BCL-xL have been used as chemotherapeutics and more recently as senolytics that selectively destroy senescent cells. That removal of senescent cells is a legitimate rejuvenation therapy that quite literally turns back aging in animal models has caused greater attention to be given to BCL-2 family proteins and their role in allowing cells to hold back apoptosis.

Separately, as noted here, evidence shows that BCL-xL is a longevity-associated protein, which is interesting, to say the least. This may or may not have anything to do with suppression of apoptosis - or if it does, one has to argue that keeping apoptosis-inclined cells alive for longer is on balance beneficial, despite being detrimental in the matter of senescent cells, or that apoptosis is complex and situational. This may be the case, but it is always challenging to tease out the specific contributions to any observed outcome of this nature. Another possibility is that greater levels of BCL-xL improve mitochondrial function in some way, but more work is needed to establish whether or not this is a plausible mechanism.

We have studied centenarians, as an example of successful aging, and have found that they overexpress BCL-xL. By performing functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC), we compared the expression patterns of 28,869 human genes in centenarians, septuagenarians, and young people. Results showed that the mRNA expression pattern of centenarians was similar to the one of young people, and completely different from that of septuagenarians. In particular, sub-network analysis of the 1,721 mRNAs that were found to be statistically different between the three populations, converged on the following six genes: interferon-γ (IFNG), T-cell receptor (TCR), tumor necrosis factor (TNF), SP1 transcription factor, transforming growth factor-β1 (TGFβ1), and cytokine IL-32.

Likewise, those six genes were related to BCL-xL, Fas, and Fas ligand (FasL), all of them known to be involved in the control of cell death regulation. However, where BCL-xL is an antiapoptotic protein, Fas and FasL are proapoptotic. This could be considered a paradox, as centenarians overexpress anti and proapoptotic proteins at the same time, but there is an explanation: BCL-xL is involved in the inhibition of the intrinsic pathway of apoptosis, which is mainly mediated by mitochondria and activated after self-cell stress; however, Fas and Fas-L induce the extrinsic pathway of apoptosis, which means that they force the cell to die after external stress signals. This suggests that centenarians have a better way to control apoptosis when cells are aging (intrinsic apoptosis), but at the same time, damaged cells by external signals are removed more efficiently (extrinsic apoptosis).

In order to further demonstrate the role of BCL-xL in longevity, we performed longevity curves using C. elegans with a gain function of Ced-9, the ortholog for human BCL-xL. Interestingly, animals overexpressing Ced-9 showed a significant increase in both the mean and the maximum survival time. Although aging is a multifactorial process, these studies suggest that BCL-xL function is relevant in aging and may be one of the factors that contributes to exceptional longevity.

Link: https://doi.org/10.3390/ijms21020418


View the full article at FightAging




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