Can Caloric Restriction Mimetics Fight Aging and Obesity at the Same Time?

Aging, at its core, is the process of gradual deterioration of the human body and its components across time. Much to our dismay, aging has long stood as an insurmountable barrier to humanity's pursuit of extended life and vitality. Current aging theories focus on key factors like metabolism, oxidative stress, mitochondrial dysfunction, and epigenetic changes. Modern technological advancements and practices have led to food surpluses across industrialized nations. However, while many of these industrial nations have solved the hunger problem, this excessive food surplus has drastically increased rates of obesity. Excessive weight gain, obesity, and increased fat mass are directly linked to higher disease and cancer rates, often exacerbated by age-related metabolic distress. Despite all of the consequences of modern living, people around the world are growing older than ever before. As a result, populations of all ages seek a wide variety of natural products and alternative approaches in the hope of living a longer and healthier life. This has prompted relentless research efforts to uncover the secrets of longevity and metabolic regulation¹.

Caloric Restriction

One of the fundamental theories regarding the aging process revolves around targeting and altering the metabolism. Caloric restriction (CR) is the process by which an organism experiences reduced caloric intake with regards to its normalized caloric requirements and is a fundamental approach in metabolic and aging research². By reducing caloric intake in various organisms, scientists have discovered a substantial correlation between increased lifespan and caloric reduction in many different organisms (e.g., mice, primates, insects, etc.)^2-4. While clinical trials have seen some success regarding CR, problems with adherence plague these studies^{2, 4}. Supportively, humans have evolved to consume and store calories and going against these innate mechanisms to willingly restrict caloric intake is, understandably, unappealing. However, metabolic modulation through caloric restriction and other means may attenuate or cure the symptoms of aging-related diseases while increasing life-span ². CR is capable of delivering many benefits including, but not limited to; increased glucose homeostasis, decreased oxidative stress, positive changes in gene expression, and increased cell proliferation⁵. Conversely, the pursuit of compounds capable of mimicking CR, known as either CR mimetics or mimics, has ensued due to the innate difficulties involved in implementing CR in clinical settings⁵.

CR Mimetics

As an alternative approach to CR, CR mimetics, both synthetic and natural, have been heavily investigated for their potential to mimic the desirable metabolic benefits of CR. Recent research has investigated novel possibilities for nutrition-based caloric restriction mimetics aimed at alleviating the adverse consequences of obesity and aging. In the following, we delve into some of the most up-to-date research and latest advancements in CR mimetics. Over the last decade, research has continually identified the potential for CR mimetics in a wide variety of tissues, organs, and metabolic processes critical to maintaining health and homeostasis across the lifespan, including but not limited to:

• Obesity/Adipose Tissue^{6, 7}
• Inflammation/Oxidative Stress⁸
• Gut Microbiota Health⁹
• Non-Alcoholic Fatty Liver Disease¹⁰
• Skeletal Muscle Function¹¹
• Glucose Homeostasis¹²
• Cardiovascular Health¹²

Within the following, I will focus on several prominent and well-studied plant-based products and compounds, highlighting their potential as CR mimetics.

Resveratrol

Resveratrol (RSV) is a plant-based polyphenol found in high concentrations in grapes that has been heavily researched for its potential as a CR mimetic¹³. RSV has continually been shown to activate SIRT1 and other sirtuin proteins, which are associated with increased lifespan and improved metabolic health, similar to the benefits observed with CR¹⁴. This activation alone may lead to various benefits, including improved insulin sensitivity, enhanced mitochondrial function, and increased fat metabolism. In direct support of this, one study discovered that RSV could potentially mimic the effects of CR through reducing plasma cytokine levels, promoting lipolysis and fatty acid uptake, and potentially inhibiting the NF-kB pathway in obese rats. This led to decreased body weight and reduced levels of inflammatory biomarkers in the fat tissue⁷. In another double-blind clinical study, trans-resveratrol supplementation altered adipocyte gene signaling and reduced the size of abdominal fat cells in obese men between the ages of 40 to 65⁶.

While RSV anti-obesogenic potential is promising, research has also shown that RSV may be capable of targeting the comorbidities of the condition such as nonalcoholic fatty liver disease (NAFLD) and CVD. A double blind randomized control trial found that daily RSV supplementation reduced inflammation and liver cell damage¹⁰. Furthermore, the study suggested that resveratrol might be more effective than lifestyle changes as an intervention strategy in patients with NAFLD¹⁰. As thoroughly evidenced, RSV supplementation can also provide potential cardioprotective benefits to the aging heart and may mitigate CVD risk factors through its anti-inflammatory, antioxidant, antiplatelet and lipid-lowering properties¹⁵. Regarding diabetes and metabolic syndrome, a recent study discovered that RSV may have contributed to a modest improvement in mouse insulin sensitivity, as evidenced by reduced fasting and post-glucose-bolus insulin levels¹⁶.

While this evidence strongly supports RSV as a CR mimetic, clinical trials investigating the effects of resveratrol have frequently produced conflicting data, making it challenging to draw definitive conclusions¹⁷. These inconsistencies and variations could be attributed to factors such as differences in dosages, the quality of RSV, study populations, and duration of treatment. However, considering the substantial evidence supporting RSV, it is relatively difficult to argue against its potential as a CR mimetic.

Green Tea Extract

Green tea extract is another plant-based supplement that has been heavily investigated for its diverse health benefits. Like RSV, green tea extract and its isolated compounds have been researched for their anti-obesogenic and CR mimetic potential¹⁸. Within these studies, evidence has shown that these compounds can reduce adiposity, improve the metabolic profile, and increase fat tissue browning in HFD fed mice¹⁸. In further support of this, green tea extract has also been shown to improve insulin sensitivity, reduce oxidative stress and inflammation, promote fat oxidation, activate sirtuin proteins and enhance cellular longevity^{19, 20}. A recent systematic review and meta-analysis of clinical trials revealed that green tea supplementation promoted significant reductions in body weight and BMI²¹. Moreover, reductions in waist circumference were notable when using green tea at doses ≥800 mg/day for less than 3 months²¹. Overall, these findings suggest that green tea can be a helpful addition to a balanced diet and exercise regimen for both aging and obese populations.

Quercetin

Quercetin, another natural plant polyphenol, has gained significant attention as a potential CR mimetic due to its unique properties. Similar to RSV, quercetin can potentially promote DNA repair and metabolic regulation through its ability to activate sirtuin proteins²². As evidenced, research has demonstrated the anti-cancer, anti-aging, antioxidant, anti-viral, and neuroprotective benefits of quercetin²³. In a most recent study, the therapeutic potential for quercetin against early stage COVID-19 was investigated. Fascinatingly, the study found that quercetin may modulate the hyperinflammatory response and increase the clearance of SARS-CoV-2 in clinical subjects²⁴.

Conclusion

Natural CR mimetics have garnered attention for their potential in addressing both aging and obesity. Compounds like resveratrol, found in grapes, and quercetin, a plant polyphenol, have demonstrated anti-aging effects by activating sirtuin proteins and promoting DNA repair. They also offer anti-obesogenic benefits by improving metabolic health, reducing inflammation, and potentially aiding in weight management. Green tea extract, another CR mimetic, has shown promise in reducing body weight, BMI, and waist circumference, making it a valuable tool for combatting obesity while potentially extending longevity. Beyond the natural CR mimetics mentioned in this article, many other natural and synthetic compounds have shown potential in age and obesity related research.

As described in the following list, you can clearly see the overlapping anti-aging potential between CR and CR mimetics.

• Metabolic Regulation (Energy Balance, Protein Synthesis, AMPK/mTOR)
  &nsp;- o CR, RSV, Quercetin, Green Tea Extract^{2, 25, 26}
• Genetic Translation and Genome Function (DNA Repair, Genome Stability, Autophagy, Cell Cycle)
  o CR, RSV, Green Tea Extract²⁷
• Oxidative Stress and Inflammation
  o CR, RSV, Quercetin, Green Tea Extract^{12, 28}

CR mimetics offer exciting avenues for future research in the quest for extended longevity and holistic approaches to improved metabolic health.

References

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