Hi, I have been studying senolytics for the last few weeks. These are my findings. These are the BCL-2 family of proteins. (BCL-2 OR "BCL family" OR BCL-xl OR BCL-W OR MCL-1 OR BCL-B OR BAX OR BAK OR BOK OR BID OR BIM OR BAD OR PUMA OR NOXA) The first five are antiapoptotic, they favor cell survival, and are frequently found on the mitochondria of cancer and senescent cells. These cells upregulate them to induce cellular survival and function. But normal cells also use them for the same purpose. p53 is known to reduce cancer, but also known to reduce survival in mice and men. The reduced activity p53 morph is found preferentially in older people.(4) p53 is a BCL-2 and BCL-xL inhibitor. p53 inhibits BCL-2 and activates BAX to promote apoptosis this prevents cancer but is life shortening. BCL-2 is longevous in humans despite causing cancer BCL-2 and BCL-xL are the major proteins inhibited by the cancer and senescent cell killing drugs dasatinib, navitoclax, and its newer cousin venetoclax. The supplements quercetin and sulforaphane are particularly efficient in doing the same, possibly with near drug like efficacy. The problem is they also kill healthy cells and likely people too. Running the above list of BCL-2 family proteins as a search string and "ANDed" with most of the cancer effective supplements we take shows them to be BCL-2 inhibitors as well. As examples methamphetamine and heroin are two BCL-2 inhibitors that cause apoptosis in brain cells. PMID: 28274858. Air pollution (PM2.5) is also a BCL-2 inhibitor. Like p53 the BCLs are major proteins striving to keep cells healthy, and associated with longevity in human studys.(12) Unfortunately one of the downsides is they are also associated with cancer. As example the major antiapoptotic protein, BCL-xL is activated by Nrf2, the cells major controller of oxidative stress.(8) The BCLs have ARE transition elements for this activation. It turns out that senescent cells have a bad reputation, possibly because they have been stressed, and are found next to leasions where they contribute to inflammation in attempts to help the immune system cope with the problem. They have both beneficial and detrimental functions. But in the bottom line they seem to be longevous. At the very least their inhibitors can no longer be seen as having a good risk/benefit ratio. I have stopped taking quercetin and sulforaphane, and will no longer try to use any senolytic products unless further strong evidence in their favor develops. In summary; senolytic interventions, while slowing cancer progression and likely eliminating senescent cells are never the less, probably detremental to human health and longevity. Thomas Astragulas, melatonin, and CAPE are claimed to up regulate BCL-xL . (4) Trade-off between cancer and longevity in humans Dumont et al. (2003) showed that in humans, replacement of arginine (Arg) by proline (Pro) at position 72 of human p53 decreases its ability to initiate apoptosis, suggesting that these two polymorphisms may differently affect longevity and vulnerability to cancer. Recently, van Heemst et al. (2005) demonstrated that individuals with Pro/Pro genotype of p53 corresponding to reduced apoptosis in cells have a significantly increased both overall survival (by 41%) and mortality (2.54 fold) from cancer along with a decreased risk of death from CVD at the ages 85+. It was suggested that in humans, p53 may protect against cancer but at a cost of longevity. One may suppose that individuals carrying alleles manifested in a lowered intensity of apoptosis in a tissue are more vulnerable to cancer but less vulnerable to stroke or myocardial infarction (MI) (Ukraintseva and Yashin, 2005). Ørsted et al. (2007) found that the overall 12-year survival was increased in p53 Pro/ Pro versus Arg/Arg homozygotes despite of potential cancer favoring properties of the former genotype. Overall, human studies indicate that it is not clear what kind of trade-off contributes more to longevity: the one between cancer and aging or the one between predisposition to cancer and other disease (such as CVD). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708086/ XX (8) Free Radic Biol Med. 2013 Apr;57:119-31. doi: 10.1016/j.freeradbiomed.2012.12.014. Epub 2012 Dec 27. Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Niture SK1, Jaiswal AK. Author information 1Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Abstract Nuclear transcription factor Nrf2 binds with the antioxidant-response element (ARE) in the promoter regions of cytoprotective genes, leading to their increased expression and cellular protection. In this study, we investigated the role of Nrf2 in the regulation of antiapoptotic Bcl-xL protein and its effect on cellular apoptosis. Treatment of mouse Hepa-1 cells with the antioxidant tert-butylhydroquinone led to the induction of Bcl-xL gene expression. Promoter mutagenesis, transfection, and chromatin immunoprecipitation assays identified an ARE between nucleotides -608 and -600 in the forward strand of the proximal Bcl-xL promoter that bound to Nrf2 and led to increased Bcl-xL gene expression. In addition, short interfering RNA (siRNA) inhibition and overexpression of Nrf2 led to a respective decrease and increase in Bcl-xL gene expression. These results implicated Nrf2 in the regulation of expression and induction of Bcl-xL protein. Nrf2-mediated expression of Bcl-xL protein downregulated Bax and decreased caspase 3/7 activity. SiRNA inhibition of both Nrf2 and Bcl-xL increased the susceptibility of cancer cells to etoposide-mediated cell death and reduced cell survival. Moreover, dysfunctional/mutant INrf2 (inhibitor of Nrf2) in human lung cancer cells failed to degrade Nrf2, resulting in increased Bcl-xL levels and increased cell survival. These data provide the first evidence of Nrf2 in the control of Bcl-xL expression and apoptotic cell death with implications for antioxidant protection, survival of cancer cells, and drug resistance. Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 23275004 PMCID: PMC3606082 related articles show it also upregulates BCL-2 XX (12) Aging (Albany NY). 2016 Oct 28;8(12):3185-3208. doi: 10.18632/aging.101078. Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging. Borras C1, Abdelaziz KM1, Gambini J1, Serna E1, Inglés M2, de la Fuente M3, Garcia I4,5, Matheu A4,5, Sanchís P6, Belenguer A6, Errigo A7, Avellana JA6, Barettino A8, Lloret-Fernández C8, Flames N8, Pes G7, Rodriguez-Mañas L, Viña J1. Author information 1Facultad de Medicina, Universidad de Valencia, Valencia, Spain, INCLIVA and Spanish Centenarian Study Group; Facultad de Fisioterapia Universidad de Valencia, Valencia, Spain. 2Facultad de Ciencias Biológicas, Universidad Complutense de Madrid, Madrid, España. 3Instituto Biodonostia, San Sebastian, Spain. 4IIKERBASQUE, Basque Foundation for Science, Bilbao, Spain. 5Servicio de Geriatría. Hospital de la Ribera. Alzira, Valencia, Spain. 6Dipartimento di Medicina Clinica e Sperimentale, Viale San Pietro 8, I-07100 Sassari, Italy. 7Instituto de Biomedicina de Valencia, IBV-CSIC, 46010 Valencia, Spain. 8Departamento de Geriatría. Hospital Universitario de Getafe, Madrid, Spain. Abstract Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl-xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl-xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of Bcl-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the Bcl-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that Bcl-xL plays an important role in exceptional aging. KEYWORDS: Bcl-2; FAS ligand; RNA; apoptosis; healthy aging; longevity PMID: 27794564 PMCID: PMC5270663 XXXX -----Original Message----- From: eightpennies To: Paul Vrana Cc: Group ; Gerontology Sent: Tue, Apr 11, 2017 10:16 am Subject: Re: [GRG] senolytics Dear All, I currently stack and cycle plant derived inhibitors of bcl-2 and other bcl antiaptotic factors in an effort to get partial clearance of my senescent cell load.