Well I know Resveratrol has been thought to extend lifespan for decades. I don't think it is the best senolytic, but close enough for me.
Between, NMN, Resveratrol and intermittent fasting i think i have healthspan and lifespan covered.
There are some adverse side effects with higher doses. I think that i would keep taking it at 300-500mg of trans-resveratrol.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164842/
Here is the whole adverse effects section from the NIH article (citations will work on the original web page):
5. Side-Effects of Resveratrol
One of the most fascinating resveratrol aspects for its future development as a promising drug is that, it does not appear to have debilitating or toxic side effects. A wide range of resveratrol doses has been used in various in vivo and in vitro studies. However, it is imperative to find out the most appropriate dose and administration route. Also, it was documented that resveratrol induces cell death in tumor tissues with relatively no effect in normal adjacent tissues [52]. Resveratrol cell uptake disparity between normal and tumor cells may be attributed to differences in available cellular targets and gene expression in cancer cells, which makes resveratrol tumor-specific. Mukherjee et al. [139] have suggested that lower resveratrol doses could be associated with health benefits, while higher doses devastate tumor cells via pro-apoptotic effects.
Resveratrol does not appear to have side effects at short-term doses (1.0 g). Otherwise, at doses of 2.5 g or more per day, side effects may occurs, like nausea, vomiting, diarrhea and liver dysfunction in patients with non-alcoholic fatty liver disease [140]. Interestingly, no major side effects were stated in long-term clinical trials [141]. In fact, resveratrol has been found to be safe and well-tolerated at up to 5 g/day, either as a single dose or as fraction of multiple-day dosing schedule [142]. However, it is imperative to mention that these studies were done in healthy populations, and that may vary in sick patients. Our understanding of resveratrol dose-dependency and administration route is further complicated, since orally administrated resveratrol gets metabolized by gut microbiota [143], which makes it difficult to determine which effects are solely due to resveratrol or both resveratrol and its metabolites.
To investigate the assumption, whether resveratrol inhibit atherosclerotic development in hypercholesterolemic rabbits, Wilson et al. [144] supplemented rabbits with or without oral resveratrol (1mg/kg), and found that resveratrol treatment did not adversely affect rabbits health other than promoting atherosclerosis. Plasma LDL electrophoretic mobility was not different between groups. Atherosclerotic lesions staining in control and resveratrol-treated groups revealed that resveratrol-treated rabbits had significantly more aortic surface area covered by atherosclerotic lesions. Therefore, resveratrol promoted atherosclerotic development, rather than protect against it, by an independent mechanism of differences observed in gross animal health, liver function, plasma cholesterol concentrations, or LDL oxidative status [144]. Ferry-Dumazet et al. [145] aiming to analyze resveratrol nephrotoxicity effects, given orally 3000 mg/kg b.w. to rats for 28 days. It resulted in nephrotoxicity documented as elevated serum blood urea nitrogen and creatinine levels, increased kidney weights, gross renal pathology changes, and an increased incidence and severity of histopathological changes in kidneys. Kidneys microscopic evaluation identified lesions whose pathogenesis could be increased by resveratrol concentration (or its metabolite) as a function of renal osmotic concentration gradients, resulting in toxic levels in renal pelvis. This would result in necrosis, renal tubules obstruction and thus tubules dilation behind obstructed region. Indeed, inflammation and pelvic epithelium hyperplasia are expected responses to the presence of necrotic tissues. Therefore, administration of 1000 or 300 mg resveratrol/kg b.w./day did not result in nephrotoxic findings. The predominant clinical signs of toxicity at 3000 mg/kg b.w./day dose group were dehydration, piloerection, and red material in cage/urine, body weight gain reduction, hyperalbuminemia, anemia (due to renal injury, which reduced erythropoietin synthesis), white blood cell counts increase due to renal pelvic inflammation. Moreover, increased ALT, ALKP and total bilirubin levels suggest liver toxicity, but this was not histologically supported. Similarly, organs evidencing weight change did not evidenced histological changes [146].
Resveratrol has been reported to both reduce cell growth and induce apoptosis in normal cells, when administered at high doses, which confirm its biphasic effects over low to high concentrations spectrum [145]. Resveratrol rapidly activate mitogen-activated protein kinase (MAPK) in a MEK-1, Src, matrix metalloproteinase, and epidermal growth factor receptor in a dependent manner. It activates MAPK and endothelial nitric-oxide synthase (eNOS) at nanomolar concentrations (i.e., magnitude less than that required for ER genomic activity) and at concentrations possibly/transiently achieved in serum following oral red wine consumption [147]. Additionally, resveratrol consumption at modest doses result in a life span increase in 1-year old mice. However, when mice consumed larger resveratrol doses (1800 mg/kg), animals were shown to die within 3–4 months [148]. Studies on steady-state pharmacokinetics and tolerability of 2000 mg trans-resveratrol, administered twice daily with food, quercetin and alcohol (ethanol) showed that trans-resveratrol was well-tolerated by healthy subjects, although diarrhea was frequently observed [149].
