Caloric restriction, fasting

To date, caloric restriction, fasting (i.e., a reduction in caloric intake without malnutrition) is the only  intervention that has consistently been found to extend  life span.  Importantly, only prolonged caloric restriction, fasting,  has been found to  increase ketogenic metabolites and to delay the onset of age-associated disease conditions such as cancer and diabetes.  In recent studies fasting  has been shown to improve a number of health outcomes including cardiac risk factors, improving insulin-sensitivity, and enhancing mitochondrial function,  to reduce oxidative damage to both DNA and RNA. Several biological mechanisms may account for the increase in health span and longevity such as downregulation of answers to oxidative stress, increased autophagy, senolysis, maintenance of a healthy population of mitochondria though biogenesis.

CR and Sirtuins  Guarente et al., [68] formulated the hypothesis that nutrient-sensing regulators mediate the effects of this diet on aging and diseases based on the findings that sirtuins were NAD+-dependent protein deacetylases and known to counter aging.  It is also clear that other nutrient sensors, such as AMPK, mTOR  and FOXO  are very important in linking diet, metabolism, and aging.

Fasting mimetics

As  fasting  is often seen as difficult, ways have been investigated to mimic fasting and caloric restriction mechanisms and their benefits. Many drugs and nutraceuticals have been studied to act as mimetics of caloric restriction, fasting which has promoted the emergence of caloric restriction fasting mimetics. Fasting mimetic compounds can be defined as compounds that mimic the protective pathways of caloric restriction and impacts the hallmarks of aging e.g autophagy and senolysis. (Fig 29). There is growing evidence that caloric restriction, fasting and fasting mimetics may trigger senolysis.

CR and fasting mimetics mimic several  molecular consequences of fasting. Main affected pathways include the SIRT, AMPK and mTOR pathway. Metformin exposure decreases mitochondrial function. AMPK inhibits glycogen synthesis, fatty acid oxidation, HMG-Co-A Reductase, and mTOR function. Decreased mTORC1 function results in increased autophagy.  Polyphenols, Spermidine, and Aspirin increase SIRT1 activity, inducing deacetylation of the RelA/p65 component and inhibit proinflammatory gene expression.  There are a number of naturally occurring polyphenols, including curcumin, resveratrol, catechins especially EGCG, gallic acid apigenin, quercetin as well as the polyamine spermidine that are discussed as CR/fasting mimetic.

Fasting Mimetic, Senolysis, Autophagy, Longevity

The scientific findings of health promoting activities of many fasting, CR- mimetics boosted a hype of often exaggerating health claims.  For resveratrol and green tea derived EGCG  beneficial effects on epigenetic regulation, epigenetic clock, autophagy, blocking effects on epigenetic histones of RNA, eg COVID-19  virus replication and attachment,  removal of senescent dangerous cells was reported.  Onion-Quercetin, apple-phloretin and curcumin epigenetic senolytic, antiviral and anti-inflammatory effects were seen. Spermidin became famous for its CR similar enhancement of autophagy, especially in neuro-inflammatory processes of cognitive decline. Many more bioactive plant ingredients became famous for their radicals-, ROS reducing activity.

Wheras any of these claims are based on solid scientifc  research often in vitro- or animal studies the use of many of these compounds are hampered by  often difficult extraction methods limiting necessary affordable amounts  of substances (e.g Spermidine), reduced  bioavailability or stability ( e.g. Resveratrol, EGCG ), or toxicological  aspects.  Often normal plant based nutrition provides more of these active compounds than supplements. For Spermidin see amounts per food here >>>

However, additives, supplements and function foods will be a way for personal health care for some consumers and research work from our group can be found here: >>>