Drug candidates and dietary supplements categorized as caloric restriction mimetics delay aging and extend healthspan and lifespan by modifying aging-associated pathways similarly to caloric restriction and intermittent fasting strategies. The term has been coined in a pivotal 1998 paper. Because caloric restriction requires continuous efforts and firm discipline, identifying active agents that produce similar but effortless effect have attracted significant attention. Such compounds would open the possibility of enhancing physiological functions, expanding longevity and lowering risk of chronic diseases. Various organic compounds have been shown to modulate anti-aging pathways in a manner similar to caloric restriction and intermittent fasting. Examples of the most widely examined caloric restriction mimetics include rapamycin, metformin, resveratrol, acarbose, aspirin, glucosamine, nicotinamide riboside, and spermidine. Rapamycin (CAS # 53123-88-9) represents one of the best-known caloric restriction mimetics. It is a macrolide compound isolated from Streptomyces bacteria. Rapamycin is an mTOR inhibitor and historically used to avoid immunosuppressive organ transplant rejection. Inhibition of mTOR is known to activate autophagy, a cellular process recognized as a powerful anti-aging approach, believed to also mediate the rapamycin effect. Rapamycin treatment has been reported to extend lifespan and to enhance health markers in model organisms. Certain reported adverse side effects such as cataract risks, infections, as well as insulin resistance restrain the use of rapamycin to delay aging and stimulate active searches for analogous mTOR inhibitors, so called rapalogs, in effort of finding potential drugs with a better safety profile. One of the first-generation rapalogs, everolimus (CAS # 159351-69-6), found within the 95% similarity limit of rapamycin by CAS SciFinder n 566 , has been approved to prevent organ rejection and for cancer treatment. Other compounds found within the 95% similarity limit of rapamycin by CAS SciFinder 566 are listed in Table . Later generation rapalog compounds are currently being examined in preclinical and clinical studies. 565 Table . Top compounds found within the 95% similarity limit of rapamycin by using CAS SciFinder n Metformin (dimethylbiguanide hydrochloride, CAS # 657-24-9), an antidiabetic drug widely used for treatment of type-2 diabetes, is also considered a caloric restriction mimetic providing anti-aging benefits, believed to be mediated by the activation of AMPK in C. elegans and rats. It has been demonstrated that metformin administration prolongs the lifespan in animal models, including mammals. In humans, metformin is shown beneficial against certain age-associated diseases, such as cancer, metabolic syndrome, as well as cognitive deficits and cardiovascular disorders. Metformin may cause adverse side effects, such as vitamin B deficiency and cognitive decline in older adults, as well as lowered testosterone levels, possibly resulting into erectile dysfunction. Resveratrol (3,5,40-trihydroxystilbene, CAS # 501-36-0), a SIRT activator, which is a natural polyphenolic phytoalexin, mostly abundant in red wine and grape skins, but also in berries and peanuts, has been widely investigated. Resveratrol has been reported to prolong lifespan and delay the onset of aging-related markers in model organisms. It also demonstrates ability to protect against an assortment of age-related disorders including type 2 diabetes, Alzheimer's disease, and cancer. A widespread opinion is that anti-aging and longevity effects of resveratrol are mediated by sirtuins activation. 577 Indeed, resveratrol has been shown to target certain stress-related cellular mechanisms, such as AMPK and SIRT1, with both targets, AMPK and SIRT1, required for resveratrol-induced health promotion. Stimulation of SIRT1 brings about protein deacetylation and autophagy induction. Other similar small-molecule SIRT1 activators have been examined including SRT-1720 (CAS # 925434-55-5) and SRT2104 (CAS # 1093403-33-8), and have been demonstrated to prolong lifespan, reducing inflammation and protecting from neurodegeneration in model organisms. Spermidine (CAS # 124-20- ) is a polyamine known to induce autophagy in various model organisms, which is considered causal for some of the reported beneficial effects. The autophagy induction is believed to be result of the inhibition of certain acetyltransferase activity by spermidine. Furthermore, spermidine is able to promote mitophagy. 585 Aspirin (acetylsalicylic acid, CAS # 50-78-2), a non-steroidal anti-inflammatory drug, has been in widespread medical use for long time. It is known to quickly metabolize into salicylate in vivo, which inhibits EP300 by competing with acetyl-CoA, thus activating autophagy and exhibiting lifespanprolonging effect in model organisms. 586