I might suggest Theaflavin, Berberine and Fisetin...
1) Theaflavin seems to be hitting the same things as Dasatinib without all the side effects.
LE's basis for thinking it works:
Scientists set out to identify a compound that would enhance quercetin’s senolytic effects by the same mechanisms as dasatinib, but without the side effects of a cancer drug. The most effective candidate they found was a group of compounds in black tea called theaflavins. In a similar way to dasatinib, theaflavins block an anti-apoptotic protein called BCL-2. If you wonder what BCL stands for, it is “B-cell lymphoma.” A compound that blocks BCL-2 might reduce risk of this common malignancy. In a mouse study, theaflavins demonstrated significant senolytic effects.
Noberini R, Koolpe M, Lamberto I, et al. Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res. 2012 Oct;66(4):363-73.
Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol. 2012 Feb;23(1):51-7.
Ting PY, Damoiseaux R, Titz B, et al. Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1. PLoS One. 2015;10(3):e0121833.
Leone M, Zhai D, Sareth S, et al. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res. 2003 Dec 1;63(23):8118-21
Han X, Zhang J, Xue X, et al. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med. 2017 Dec;113:59-70.
Cameron AR, Anton S, Melville L, et al. Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a. Aging Cell. 2008;7(1):69-77.
Caruana M, Vassallo N. Tea Polyphenols in Parkinson’s Disease. Adv Exp Med Biol. 2015;863:117-37.
Chen SQ, Wang ZS, Ma YX, et al. Neuroprotective Effects and Mechanisms of Tea Bioactive Components in Neurodegenerative Diseases. Molecules. 2018;23(3).
Peng C, Chan HY, Li YM, et al. Black tea theaflavins extend the lifespan of fruit flies. Exp Gerontol. 2009;44(12):773-83.
Aizawa T, Yamamoto A, Ueno T. Effect of oral theaflavin administration on body weight, fat, and muscle in healthy subjects: a randomized pilot study. Biosci Biotechnol Biochem. 2017;81(2):311-5.
2) Berberine is a potent mTOR1 inhibitor without R's nasty side effects.
Berberine sensitizes rapamycin‑mediated human hepatoma cell death in vitro
Recent research has demonstrated that berberine has anticancer activity against various types of cancer, mediated through the suppression of mammalian target of rapamycin (mTOR). The present study aimed to investigate the in vitro synergistic anticancer effect of combined treatment of rapamycin at various concentrations (0, 10, 50, 100 and 200 nM) and berberine (62.5 µM) in SMMC7721 and HepG2 hepatocellular carcinoma (HCC) cell lines, and the potential underlying molecular mechanism. The combined use of rapamycin and berberine was found to have a synergistic cytotoxic effect, with berberine observed to maintain the cyotoxic effect of rapamycin on HCC cells at a lower rapamycin concentration. Moreover, the cells treated with the combination of the two agents exhibited significantly decreased protein levels of phosphorylated (p)‑p70S6 kinase 1 (Thr389), the downstream effector of mTOR, compared with the cells treated with rapamycin or berberine alone. Furthermore, overexpression of cluster of differentiation (CD) 147, a transmembrance glycoprotein associated with the anticancer effects of berberine, was found to upregulate p‑mTOR expression and inhibit cell death in SMMC7721 cells co‑treated with rapamycin and berberine. In conclusion, the findings of the present study suggest that the combined use of rapamycin and berberine may improve HCC therapy through synergistically inhibiting the mTOR signaling pathway, which is at least in part, mediated through CD147.
Looks like berberine maybe a cheaper and safer mTOR1 inhibitor all on its own: Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression BBR extended the lifespan of chemotherapy-treated mice and naturally aged mice by ~52% and ~16.49%, respectively. The residual lifespan of the naturally aged mice was extended by 80%, from 85.5 days to 154 days. The oral administration of BBR in mice resulted in significantly improved health span, fur density, and behavioral activity. Therefore, BBR may be an ideal candidate for the development of an anti-aging medicine.
More fun reading Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK/mTOR signaling pathway ("...new insight into berberine’s molecular mechanism and its therapeutic potential in the treatment of atherosclerosis.) Berberine Induces Autophagic Cell Death in Acute Lymphoblastic Leukemia by Inactivating AKT/mTORC1 Signaling (We find BBR caused ALL (Acute Lymphoblastic Leukemia) cell death by inducing autophagy. We also investigate the underlying mechanism responsible for BBR-induced autophagy. The findings will provide crucial insight into the application of BBR on ALL treatment.)
Looks like probably liposomal berberine is needed to improve absorption, or, maybe just the right microbiome: Transforming berberine into its intestine-absorbable form by the gut microbiota; or, if you have a lab; d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble form of vitamin E and is comprised of a hydrophilic polar head and a lipophilic alkyl tail resulting in amphiphilic properties for improving bioavailability.
3) Fisetin is effective all by its self and has no nasty side effects. (too much evidence to post - see the fisetin thread.)
LongeCity
