Forever young and healthy?

Lifespan and healthspan effects of caloric restriction mimetics

KEY POINTS

• To date, CR is the most thoroughly and successfully researched method to increase both – lifespan and healthspan – in a broad range of animals and non-human primates.

• Caloric restriction (CR) is a significant, sustained reduction of continued caloric intake from baseline levels.

• There is no direct human evidence of lifespan extension in humans from CR, yet. But the reduction of caloric intake by 30‒40% in animal models resulted in longevity increases by 40% or more.

• The health benefits of chronic caloric restriction resulting in lifespan extension are well established in many short-lived species.

Longevity increases by 40% or more

There is no direct human evidence of lifespan extension in humans from CR yet. But the reduction of caloric intake by 30‒40% in animal models resulted in longevity increases by 40% or more. The health benefits of chronic caloric restriction resulting in lifespan extension are well established in many short-lived species.

As reported in Nature in 2018 (Pifferi, F., Terrien, J., Marchal, J. et al. - Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Commun Biol 1, 30, 2018), a cohort of grey mouse lemurs (Microcebus murinus, lemurid primate) was exposed to a chronic moderate (30%) caloric restriction. Compared to control animals, caloric restriction extended lifespan by 50% (from 6.4 to 9.6 years, median survival), reduced aging-associated diseases, and preserved loss of brain white matter in several brain regions.

However, caloric restriction accelerated the loss of grey matter throughout much of the cerebrum. Cognitive and behavioral performances were, however, not modulated by caloric restriction.

Risk factors for age-related diseases moderate

The NIA (National Institute of Ageing) funded CALERIE study revealed significant reductions in risk factors for age-related diseases such as cardiovascular disease, diabetes, and some cancers from moderate CR.

CR has been defined as a long-term 30‒40% reduction in calories. Still, some health benefits in humans have already been observed at less-restrictive caloric reduction levels ranging from 16 to 25 percent and from weeks to months.

The exact mechanisms as to how and why CR works in humans are not yet fully understood. But research points to the direction that CR may reduce oxidative damage, increasing cellular repair, lowering the production of inflammatory cytokines, or by promoting hormesis, a mild form of stress that stimulates cellular protection. CR in humans also reduces fasting insulin levels and lowers resting body temperature, two important biomarkers for delaying aging.

By the way: The frequency of meals seems to be of no relevance for CR to work, at least in animal models. Lifespan extensions in rodents have been observed at meal frequencies ranging from six times a day to three times per week.

Several compounds and nutrients are currently being researched that may mimic the effects of CR without requiring embarking on a strict diet and a reduction in calorie intake. These include resveratrol, metformin, green tea polyphenols, aspirin, PQQ, and branched-chain amino acids.

Caloric Restriction Mimetics

Maintaining a dramatically reduced caloric intake over the long term can be very demanding. Few people are willing to reduce their caloric consumption by 30‒40% to meet the classic CR definition, and even the less restrictive protocols (16‒25%) used in human interventions have not been satisfied with full compliance.

The search for an alternative or complement to CR has involved the identification or development of compounds that mimic some of the physiological or gene-expression changes associated with CR, without the requirement of lowered caloric intake or loss of body weight. While many compounds can be broadly interpreted as CRMs, a more focused definition of CRM would be a compound or intervention that mimics the metabolic, hormonal, or physiological effects of CR without reducing long-term food intake, while stimulating maintenance and repair processes, and producing CR-like effects on longevity and reduction of age-related disease.

Curcumin, Green Tea, and Ginkgo Biloba

Several compounds have been investigated as CRMs, encouraging preliminary results in animal models. Tetrahydrocurcumin (a curcumin metabolite) and green tea polyphenols have demonstrated increases in average and maximum lifespans in mice.

The effects were observed when the mice received treatments by month 13 (if given later in life, the treatments had no effect on lifespan), and in the case of green tea extract, the treatment had no effect on body weight. An investigation of Ginkgo Biloba on cognitive behavior in male Fischer rats revealed an unexpected, statistically significant increase in average lifespan when compared to controls (26.4 vs. 31.0 months).

The NIA Aging Intervention Testing program, a multi-center study on longevity-enhancing compounds, has already identified life-extending or CR mimetic activities in rapamycin and aspirin in rodents and is currently testing other potential compounds, including medium-chain triglycerides, caffeic acid esters, and curcumin.

Resveratrol and Pterostilbene

Stress-induced plant compounds can stimulate stress responses in other species, and this cross-species hormesis is called xenohormesis. Xenohormesis may have evolved as an early warning in animals about impending environmental changes (such as scarcity in the food supply), allowing them to adapt accordingly. The most familiar of these stress-inducing compounds is resveratrol, well-known for its presence in grape skin but present at detectable levels in several plant species. Resveratrol simulates CR123 in the absence of actual nutrient deficiency by activating sirtuins (SIRT1 is the human homolog) and has been shown to increase lifespan in fungi, nematodes, flies, fish, and mice. SIRT1 also suppresses NF-kB (and the inflammatory cytokines and enzymes NF-kB activates), lending resveratrol anti-inflammatory activity in cell culture and animal models. High-dose resveratrol reduced IGF-1 levels in healthy human volunteers, a chemopreventative activity associated with CR. Pterostilbene, a methylated analog of resveratrol from blueberries, similarly attenuates inflammation in a CR-like manner, reducing NF-kB signaling and COX-2 activities in cell culture.

Fisetin, Quercetin, and Theaflavins

Other plant-derived polyphenolic compounds (such as catechins, curcumin, or flavonoids) may also have xenohormesis activities; it has been suggested that most health benefits from plant phytochemical consumption might not be from their antioxidant properties but rather by a CR-like modulation of stress-response pathways.

Fisetin, quercetin, proanthocyanidins, and theaflavins are compounds that have inherent chain-breaking antioxidant chemistries but appear to exert profound health effects unrelated to their ability to quench free radicals. Fisetin and quercetin have been shown to stimulate SIRT1, a central activity of CR. In vitro, fisetin, like CR, reduced mTOR signaling, Nf-kB activation, and COX-2 gene expression and activated antioxidative and detoxifying gene pathways (Nrf2). Fisetin has also been shown to increase lifespan in Saccharomyces and Drosophila. Quercetin, in addition to proanthocyanidins from grape seed, has also been shown to reduce the production of inflammatory cytokines and the expression of vascular endothelial growth factor (VEGF), which may prevent tumors from recruiting blood vessels. This same chemoprotective activity has been observed in rats under CR. Theaflavins are flavan-3-ols from black tea produced during tea leaves' oxidation (fermentation). Aside from suppressing NF-kB and inflammatory cytokines in vitro and mice and their induction of apoptosis in cancer cells, theaflavins also stimulate the longevity factor Forkhead box 1 (FOXO1) in invertebrate and mammalian cells.

Nicotinamide Riboside

Nicotinamide riboside is another naturally-occurring compound that may act as a CRM. It is a source of vitamin B3 and a precursor for nicotinamide adenine dinucleotide (NAD+), a molecule involved in many biological processes. NAD+, one of the necessary biologically active forms of NAD, is required to activate proteins called sirtuins, including SIRT1, that regulate cellular metabolism and DNA transcription. NAD+ levels decrease with age, resulting in lower sirtuin activity. This may contribute to dysfunction in cell nuclei and mitochondria and to a range of age-related disorders.

Like calorie restriction and exercise, nicotinamide riboside can increase NAD+ levels and SIRT1 activation and may be able to prevent or reverse age-related mitochondrial and metabolic dysfunction and disease. In cultured yeast cells, nicotinamide riboside supplementation raised NAD+ levels and increased lifespan without calorie restriction. Even in mice on a high-fat diet, nicotinamide riboside supplementation was found to raise NAD+ levels and SIRT1 activity and was associated with positive metabolic effects, including less weight gain, improved exercise performance, and decreased liver fat.

Metformin and Cinnamon

The glucoregulatory agent metformin can produce many of the gene expression changes found in mice on long-term CR; in particular, it can decrease the expression of chaperones; a set of proteins that, in addition to their other functions, can reduce apoptosis (self-destruction of damaged or malignant cells) and promote tumorigenesis. Metformin has increased the mean lifespan in the worm C elegans. Along with the related anti-diabetic biguanide drugs phenformin and buformin, metformin extended the mean life span of mice by up to 37.9% and their maximum life span by up to 26% in multiple studies while significantly decreasing the incidence and size of mammary tumors. However, these effects on spontaneous tumor incidence were limited to female animals. Metformin’s CR-like results are possibly due to the influence on insulin or IGF-1 signaling. This mechanism may also explain the lifespan extension properties of the glucoregulatory herb Cinnamomum cassia (cinnamon bark) in C. elegans.

Gynostemma pentaphyllum and Hesperidin

Numerous studies have found that metformin, which can induce a calorie restriction-like state, activates a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK). This enzyme, which affects glucose metabolism and fat storage, has been called a “metabolic master switch” because it controls numerous pathways related to extracting energy from food and storing and distributing that energy throughout the body.

Gynostemma pentaphyllum (G. pentaphyllum) is used in Asian medicine to promote longevity. Its longevity effects appear to be due, in part, to its ability to activate AMPK.161 Studies of G. pentaphyllum supplementation in humans demonstrate results also found in calorie restriction, such as improved glucose metabolism and reduced body weight, abdominal fat, and overall fat. Other studies found that G. pentaphyllum significantly improves insulin sensitivity, a mechanism also observed in studies of CR.

Hesperidin and related flavonoids are found in various plants, especially citrus fruits, and peels. Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity. Animal and in vitro research findings suggest that hesperidin’s positive effects on blood glucose and lipid levels may be related partly to the activation of the AMP-activated protein kinase (AMPK) pathway. Accumulating evidence suggests hesperidin may help prevent and treat several chronic diseases associated with aging.

Hesperidin may protect against diabetes and its complications by activating the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury. Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had a 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level.

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin, and placebo assignments were reversed. Hesperidin treatment improved endothelial function, suggesting this may be a critical mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and significant decreases in total cholesterol apolipoprotein B (ApoB) and markers of vascular inflammation relative to placebo. In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and decreased markers of vascular inflammation. Another controlled clinical trial included 75 heart attack patients randomly assigned to receive 600 mg of hesperidin per day or a placebo for four weeks. Those taking hesperidin significantly improved high-density lipoprotein (HDL) cholesterol levels and markers of vascular inflammation, fatty acid, and glucose metabolism.

Fish Oil

Fish oil, while not a CRM, appears to increase the efficacy of CR at preventing free radical damage; fish oil feeding with 40% CR in mice demonstrated synergistic reductions in thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and was more effective at reducing inflammatory markers (COX-2 and iNOS expression) that CR or fish oil alone.

The branched-chain amino acids (leucine, isoleucine, and valine) exhibit several CR-like properties related to mitochondrial biogenesis. Leucine increased mitochondrial mass in cultured human myocytes (muscle cells) and activated genes associated with CR (PGC-1α and SIRT-1). Elevations in CR gene expression were observed in mouse cardiomyocytes using a mixture of all three BCAAs.151 The BCAAs also have an extended lifespan in Saccharomyces and mice when supplied above typical dietary levels. Similarly, pyrroloquinoline quinone (PQQ), a bacterial electron carrier and cofactor for several bacterial enzymes (and at least one mammalian enzyme), increased mitochondrial DNA content and stimulated oxygen respiration (both indicative of biogenesis) in cultured mouse hepatoma cells through the activation of the CR gene PGC-1α.