Caloric Restriction Mimetics in Health & Longevity

Caloric restriction is one of the most well-researched interventions for improving health and lengthening lifespan. Until recently, the only way to achieve caloric restriction was to reduce calorie intake by 30-40%. Sometimes, it requires a strict diet which is challenging for many people.

But, what if you could have the benefits of a restricted diet without actually restricting your diet?

A new class of innovations known as caloric restriction mimetics has emerged that allow people to enjoy the benefits of caloric restriction. These benefits are purportedly: Reversing the ageing process and improve health without extreme dietary restrictions that could take away from the enjoyment of life.

What are caloric restriction mimetics and how do they work?

Calorie restriction mimetics (CRM) are compounds that can imitate calorie restriction's significant health and anti-aging benefits.

A more specific definition would be:

Researchers are investigating whether calorie restriction promotes a long and healthy life by causing alterations in one or more biological pathways linked to healthy aging. Biological pathways are sequences of chemical processes within and across cells, similar to a factory's production line. Pathways are like sets of instructions required to complete a task involved in cell function. For example, one pathway may promote the development of a new cell, the destruction or repair of a damaged cell, the transmission of signals along the nerves, the synthesis of a hormone, or the activation of a gene to activate a different pathway.

An excellent health status is dependent on properly-functioning pathways. People with dysfunctional pathways are more prone to illnesses and accelerated aging. Research on calorie restriction mimetics seeks to explore possible alternatives that target the same beneficial pathways that caloric restriction activates, with the objective of extending lifespan, defined by how long individuals live in good health.

Image source: Tucci P. Caloric restriction: is mammalian life extension linked to p53?

Four key biological pathways are highlighted as mechanisms for CRM benefits:

1. Insulin signaling pathway. This pathway is a series of events that occur in the body when you eat. Insulin is released in response to the presence of glucose in the circulation. Insulin signaling controls whether glucose will be utilized right away or saved for later use, including where it is going to be stored. Impaired insulin signaling may result in glucose mismanagement and age-related illnesses like diabetes and heart disease. [1]
   
   
2. mTOR pathway. This pathway can tell whether nutrients are available and accessible. It stimulates cell development when it recognizes sufficient nutrition and activates the stress response when it senses a deficiency of calories (which happens with calorie restriction). In effect, this improves the cell's capacity to heal itself as well as its resistance to toxins and other environmental stressors. [2]
   
   
3. SIRT1 pathway. Sirtuins are a family of enzymes that play a role in metabolic control and cellular health. They can boost the cellular synthesis of mitochondria, which are the cell's powerhouses. SIRT1 is the most studied protein among the sirtuins, and signaling via the SIRT1 pathway helps cells withstand stress and thrive. [1]
   
   
4. AMPK pathway. The AMPK pathway is a signaling pathway that involves the AMP-activated protein kinase (AMPK), an enzyme that helps cells stay stable by initiating processes that aid in utilizing their energy more efficiently even when there is low energy reserve. [2]

Calorie restriction reduces the activities of insulin signaling and mTOR pathways while stimulating the SIRT1 and AMPK pathways. Researchers are hunting for chemicals that might suppress or boost these activities in a similar way.

What are the benefits of caloric restriction mimetics for health & longevity?

The demand for therapies to address aging-driven defects and age-related illnesses has never been stronger. With the continuously-increasing aging population amid a rising prevalence of non-communicable diseases, strategies to combat these conditions are needed. CR and CRMs, in particular, are two interventions that are currently on the spotlight.

CR is presently the only intervention that has been shown to extend a person's maximum lifespan. CRMs, on the other hand, may be utilized instead of true CR, making it more practical. Some of the promising outcomes from CR mimetic experiments are shown in the image below.

• CRMs increase the mean and maximum lifespan in the healthy state.
• CRMs reduce the risks of metabolic disorders (anti-diabetic and liver protection).
• CRMs alleviate symptoms of neurological and neuropsychiatric conditions.
• CRMs have anti-cancer properties.
• CRMs boost immunity and fight inflammation.

Effects of caloric restriction mimetics seen in clinical studies
Image source: Madeo F, Carmona-Gutierrez D, Hofer SJ, Kroemer G. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential.

Related: Biohacking for Longevity: 4 Ways to Stay Healthy All Throughout Life

Supplements, dietary and non-dietary strategies as caloric restriction mimetics

Scientists are testing a variety of drugs and experimental chemicals to determine whether they have comparable effects to calorie restriction, based on existing understanding of important pathways associated with it. Pharmaceuticals, nutraceuticals (food-derived compounds), plant extracts, and body-produced molecules, including hormones, peptides, and amino acids, are all studied as supplements. In addition, dietary and non-dietary interventions are also being investigated as CRMs.

The following are the top and most-studied CRM supplements

Curcumin, ginkgo biloba, and green tea

In animal models, curcumin and polyphenols from tea increased lifespans [3]. Another principal component of green tea is epigallocatechin gallate (EGCG). EGCG can enhance the lipid metabolism pathway, activates a “fat-burning” effect, and can be used as a supplement for weight loss [4].

When compared to controls, a study investigating the effects of ginkgo biloba on cognitive behaviour in male rats found an unexpected increase in average longevity (26.4 vs. 31.0 months) [5].

In rats, the National Institute of Aging (NIA) Aging Intervention Studying program is now testing additional promising substances such as curcumin, caffeic acid esters from coffee and medium-chain triglycerides.

Related: The Health Benefits of Turmeric

Resveratrol and pterostilbene

Stress-induced plant compounds have also been observed to have beneficial effects as CRMs. The most well-known of these chemicals is resveratrol, which is found in grape skin but also in a number of plant species in minimal amounts.

Resveratrol can activate the sirtuins (SIRT1), simulating CR and has been found to extend longevity in various animal models. [6] SIRT1 reduces pro-inflammation NF-kB activity hence, resveratrol has anti-inflammatory properties. In healthy human volunteers, high-dose resveratrol lowered the insulin-like growth factor levels, a chemopreventative effect linked to CR. [7]

Pterostilbene, a methylated counterpart of resveratrol found in blueberries, inhibits inflammation in a CR-like way in cell culture, lowering NF-kB activation and COX-2 activity, which are both responsible for the progression of inflammation. [8]

Fisetin, quercetin, and theaflavins

Fisetin, quercetin, and theaflavins are examples of plant-derived antioxidants that have protective effects on cells against damages from free radicals, the unstable molecules generated during normal metabolism. Both fisetin and quercetin have been reported to increase SIRT1, a key CR-induced molecule. [9]

Fisetin inhibits undesirable effects of mTOR signaling, NF-kB activation, and COX-2 gene expression in vitro, similar to CR, and activates the antioxidative and detoxifying gene pathways. Fisetin has also been demonstrated in yeast and fly models to extend longevity. [10]

In addition to grape seed-derived proanthocyanidins, quercetin has been demonstrated to inhibit the production of inflammatory cytokines and the expression of the famous cancer promoter called vascular endothelial growth factor (VEGF), hence it has the capacity to prevent tumor growth. [11]

Compounds formed during the fermentation of black tea leaves are known as theaflavins. Theaflavins promote lifespan extension in invertebrate models and suppress the NF-kB inflammatory pathway in mice. [12]

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN)

Two other naturally-occurring molecules that may serve as a CRM are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). These molecules are precursors to nicotinamide adenine dinucleotide (NAD+), a cellular chemical which is a coenzyme required in a lot of biological activities.

Cymbiotika’s NMN with added polyphenols and antioxidants can significantly boost NAD levels throughout the body.

NAD+, one of the most physiologically active forms of NAD, is a required fuel for the activation of the sirtuin, which control cellular metabolism and DNA repair. [13]

Aging is correlated with lower NAD+ levels, which results in reduced sirtuin activity. This may have an impact on cell nucleus and mitochondrial malfunction, as well as in a variety of age-related diseases. [14]

Even without caloric restriction and exercise, NR and NMN both can boost NAD+ levels and SIRT1 activation, similar to calorie restriction and exercise, and may be able to prevent or treat age-related mitochondrial and metabolic malfunction. NR supplementation was shown to increase NAD+ levels and SIRT1 activity in mice on a high-fat diet, and was linked to good metabolic outcomes such as reduced weight gain, greater exercise performance, and lower liver fat. [14] On the other hand, NMN can enhance telomere length making it a very exciting candidate to retard the aging process. [15]

Finally, NMN may be a better choice since NR is unstable in the bloodstream, while NMN is an orally-bioavailable form. [16]

Cinnamon and metformin

Many of the gene expression changes seen in mice on long-term CR can be attributed to the glucoregulatory agent called metformin. Metformin can lower the expression of chaperones, a group of proteins that, among other things, can reduce cell death and promote the formation of tumor cells. [17]

In the worm C. elegans, research shows that metformin can extend its average lifespan. CR-like effects of metformin might be attributed to its impact on insulin or IGF-1 signaling. This method may also explain why another glucoregulatory intervention using the herb Cinnamomum cassia (cinnamon bark) can also extend the lifetime of C. elegans. [18]

Hesperidin

Citrus fruits, particularly their peels, contain hesperidin and similar flavonoids, which can also be found in a range of plants. Upon digestion, hesperidin is converted to hesperetin and other metabolites. These substances are potent antioxidants with lipid-lowering, anti-inflammatory, and anti-diabetic properties. [19]

The favorable effects of hesperidin on blood glucose and lipid levels may be connected in part to activation of the the AMPK pathway, which regulates glucose metabolism and fat storage. Additionally, hesperidin may help prevent and treat a variety of chronic disorders linked to aging. [20]

Fish oils

While fish oil is not a CRM, it appears to enhance the efficacy of CR by enhancing the antioxidant effect. Feeding mice with fish oil and 40% CR showed synergistic reductions in free radicals and was more effective in reducing inflammation compared to CR or fish oil alone. [21]

Branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine are found in fish oil. These BCAAs have a number of CR-like characteristics and are especially important for cellular maintenance. In cultured human muscle cells, leucine can enhance the mitochondrial mass and activate genes that are linked to CR including SIRT-1. When given in excess of typical dietary amounts, BCAAs have been shown to enhance longevity in yeast and mice. [22]

Looking for a vegetarian alternative? Try Primal Collective Marine Algae - a plant-based formidable non-fish Omega 3 DHA/EPA supplement.

Related: Why Fish Oil is Our Evolutionary Companion and How We Became Estranged

Rapamycin

In animal models, the use of the mTOR inhibitor rapamycin was observed to result in an increase in the subjects' total lifespan. In mice models of various age-related disorders, including Alzheimer's disease, cardiovascular disease, and different malignancies, it was shown that rapamycin could delay the development of these conditions. [23]

It is believed that the cellular activities it caused are similar to those caused by calorie restriction. [24] The possibility that it may be used as a therapy for anti-aging in human is of significant interest.

Berberine

Berberine is a compound found in a variety of plants, notably the barberry bush. Berberine's main selling point as a weight-loss supplement is its ability to reduce the efficiency of cellular energy generation.

In general, when cells can create cellular energy more efficiently, a bigger proportion of nutrients are converted into large energy reserve. This gives them more chemical energy than they may need to carry out their physiological functions. Adipocytes, which are the fat cells, are formed when cells accumulate extra energy. [25]

Therefore, reducing the efficiency of cellular energy production results in a lesser surplus of energy beyond what the cell requires. To put it another way, there is less chemical energy that is turned to fat.

Furthermore, sirtuin activity induces autophagy, which protects liver function, has neuroprotective benefits, and reduces heart damage in animal models. [26] Berberine has also been proven to promote longevity, enhance insulin parameters, and have hypoglycemic effects in type 2 diabetic patients. [27]

Spermidine

Spermidine is a naturally occurring polyamine that may be found in every living body. It plays an important role in the maintenance of cellular homeostasis by initiating autophagy in a variety of model species. [28, 29] Its role as a CRM enables it to modulate inflammation and confer neuroprotection.

Supplementing with spermidine was also shown to enhance the molecular activities related to living longer. In addition, it can inhibit the growth of cancer cells, metabolic diseases, cardiovascular diseases, and neurodegenerative disorders. [30]

If you are Celiac, have Leaky Gut or SIBO, are on an Autoimmune Paleo or Lectin-free diet, or are gluten sensitive, Oxford Healthspan offers a gluten-free spermidine supplement - Primeadine GF. It is also suitable for vegans and vegetarians.

Those who want to take their autophagy to the next level can take Primeadine GF in the morning and Primeadine Original in the evening or before bed to help gut biome produce its own spermidine at night.

Dietary interventions can also be used as a form of CRM

Intermittent fasting

Intermittent fasting is a kind of eating regimen in which you alternate between fasting and eating on a regular basis. Studies have shown that intermittent fasting can help people lose weight and prevent— or even reverse—illness.

It may help to control blood sugar levels, boost stress resistance, reduce inflammation, improve resting heart rate, brain health, and cognition by lowering blood pressure and cholesterol levels. [31]

To learn more about fasting - read "Fast This Way" by Dave Asprey

Ketogenic diet

Weight loss is the direct result of following a ketogenic diet. People often say they feel less hungry on this diet than they do on other restrictive diets. Since fats take a long time to break down in the body, people feel less hungry with fatty meals. Weight loss occurs not just as a result of ketosis but also as a result of calorie restriction and the elimination of other dietary categories.

In children with epilepsy, the keto diet may help decrease seizures. It is also used by endurance athletes and bodybuilders to burn fat quicker than caloric restriction method. Other potential benefits of ketogenesis include protection against cardiovascular diseases, diabetes, and cancer. [32]

Need help fueling your body while on keto - check a full range of ketogenic supplements on OptimOZ

Non-dietary interventions are also being investigated as CRMs

Sauna

Inside the sauna, blood pressure and heart rate rise comparable to the effect of a short-to-moderate workout. Saunas imitate the physiological effects of moderate exercise and have been linked to improved joint health, lower blood pressure, lower mortality, enhanced immune function, and a reduced risk of cardiovascular disease. [33]

Cold exposure

Human health is influenced by the thermal environment, and regular moderate cold exposure, in particular, may have a major impact on our energy consumption over long periods of time. Cold temperatures can generate more "brown fat," a healthier type of fat tissue that is particularly good at thermogenesis and burning calories. [34]

Additionally, cold exposure has been found to have beneficial effects on increasing metabolic rate and improving insulin sensitivity, offering a potential prevention and treatment strategy for type 2 diabetes. [35]

Conclusion

Overall, caloric restriction mimetics (CRMs) help protect cells for over-all health, slow down or even reverse aging-driven defects, and are very promising for boosting longevity.

While more research is needed in order to determine the full potential of these substances, it’s no doubt that they’re at the forefront of an era that levels up the current strategies in fighting age-related diseases and improving overall well-being.

If you want to optimize your body and reap the benefits of caloric restriction without strict diet constraints, CRMs may be the answer you’ve been searching for.

Reference:

1 - https://pubmed.ncbi.nlm.nih.gov/34552954/
2 - https://pubmed.ncbi.nlm.nih.gov/22983298/
3 - https://pubmed.ncbi.nlm.nih.gov/17516143/
4 - https://pubmed.ncbi.nlm.nih.gov/26093535/
5 - https://pubmed.ncbi.nlm.nih.gov/9469738/
6 - https://pubmed.ncbi.nlm.nih.gov/17980602/
7 - https://pubmed.ncbi.nlm.nih.gov/20436227/
8 - https://pubmed.ncbi.nlm.nih.gov/19447859/
9 - https://pubmed.ncbi.nlm.nih.gov/12939617/
10 - https://pubmed.ncbi.nlm.nih.gov/15254550/
11 - https://pubmed.ncbi.nlm.nih.gov/19139005/
12 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033565/
13 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616234/
14 - https://pubmed.ncbi.nlm.nih.gov/24786309/
15 - https://www.frontiersin.org/articles/10.3389/fnut.2021.756243/full
16 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807296/
17 - https://pubmed.ncbi.nlm.nih.gov/16189280/
18 - https://pubmed.ncbi.nlm.nih.gov/20179756/
19 - https://pubmed.ncbi.nlm.nih.gov/25109791/
20 - https://pubmed.ncbi.nlm.nih.gov/25675136/
21 - https://pubmed.ncbi.nlm.nih.gov/16438990/
22 - https://pubmed.ncbi.nlm.nih.gov/19500359/
23 - https://www.sciencedirect.com/science/article/pii/B9780124115965000022
24 - https://www.sciencedirect.com/science/article/pii/B9780128159620000111
25 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345941/
26 - https://pubmed.ncbi.nlm.nih.gov/30840912/
27 - https://pubmed.ncbi.nlm.nih.gov/30563192/
28 - https://pubmed.ncbi.nlm.nih.gov/29371440/
29 - https://pubmed.ncbi.nlm.nih.gov/30306826/
30 - https://pubmed.ncbi.nlm.nih.gov/32979155/
31 - https://pubmed.ncbi.nlm.nih.gov/31881139/
32 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153354/
33 - https://pubmed.ncbi.nlm.nih.gov/31126559/
34 - https://pubmed.ncbi.nlm.nih.gov/24462079/
35 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506100/