Best Supplements to Reverse the 12 Hallmarks of Aging.

In the early 1900s, life expectancy was around 50 years, but today it’s more than or over 80 years. Possible contributors to this trend include developments in medical treatment and the promotion of cleaner, safer, and healthier living environments.

Numerous chronic illnesses, such as those affecting the brain and blood vessels, include age as a key risk factor. Therefore, aging processes have been proposed as possible targets for developing innovative and generally effective preventatives or treatments and supplements.

Mankind’s medical progress has come a long way, but there’s still one thing it can’t do: keep us from aging.

Recent research has uncovered mounting evidence for the existence of a “metabolic clock” that regulates the aging process. Changes to metabolism add up over time, leading to a loss in metabolic balance and overall health and vitality as the clock ticks. To combat aging and increase longevity, it is essential to treat its root causes.

Loss of proteostasis, mitochondrial dysfunction, altered nutrient sensing, telomere attrition, genomic instability, cellular senescence, stem cell exhaustion, epigenetic alterations, and altered intercellular communication have all been categorized as “hallmarks of aging” that are thought to contribute to the aging process.

This approach is beneficial since these medications have previously undergone extensive testing for both safety and efficacy in humans and are used daily in clinical settings. Two of them, in particular, such as rapamycin and metformin, have shown a lot of promise in recent research.

But more research is going to focus on reversing the hallmarks of aging. A few of the most studied supplements are,

1. SPD Spermidine

A naturally occurring polyamine called spermidine has been found to have anti-aging effects. Supplements of spermidine extend life, boost stress tolerance, and reduces the onset of age-related disease and movement impairment.

Autophagy, the process of cellular regeneration, is stimulated by spermidine and is responsible for the improvement in the hallmarks of aging. It has the effect of a calorie regulation mimetic (CRM), which means it makes the body react as if it were fasting.  It has also been studied in different research to reduce 12 hallmarks of aging.

	Hallmarks of Aging
Spermidine	Genomic instability Telomere attrition Epigenetic alterations Loss of proteostasis Disabled macroautophagy Deregulated nutrient-sensing Mitochondrial dysfunction Cellular senescence Stem cell exhaustion Altered intercellular communication Chronic inflammation Dysbiosis

This causes autophagy through the TOR kinase pathway, which controls the metabolism of cells and balances the nutrients available when cells are under nutrient tension. During autophagy, cells use their damaged organelles to renew themselves, which is thought to have many anti-aging benefits.

Spermidine protects neurons against inflammation, ischemia, and oxidative stress. Autophagy plays a role in this process by breaking down amyloid-beta proteins. As they accumulate, these plaques in the brain are linked to neurodegenerative disorders like Alzheimer’s. Research suggests that spermidine may be able to delay or even halt the progression of dementia in older adults.

Research called “Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions” found that spermidine increased telomerase activity in human hair follicle cells. Telomerase is an enzyme that adds DNA to telomeres to stop them from getting shorter.

Additionally, spermidine has been linked to enhanced fertility in both sexes.

2. RSV Resveratrol

Resveratrol is a compound that has recently gained attention as a possible anti-aging treatment by influencing the major hallmarks of aging. According to several animal research, resveratrol influences aging, the onset of age-related illnesses, and longevity.

Human Trials. 

Recent studies lend credence to the idea that resveratrol can extend the lifespan of cells by activating proteins in the cell called sirtuins. Researchers identified natural and synthetic substances, including resveratrol, to stimulate proteins in the past.

Dr. David Sinclair of Harvard Medical School and colleagues found that resveratrol stimulated sirtuins directly; he was on the team that first discovered this effect in 2003. Resveratrol appears to aid in increasing the activity of mitochondria, which provides energy within cells and may, therefore, reduce the hallmarks of aging.

Different routes of action allow resveratrol to influence a wide range of biological processes, with potential effects on oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, survival, and angiogenesis.

 

Resveratrol’s effect on the hallmarks of aging has been tabulated below, as it has been found in 2022 research to reduce 9 out of 12 hallmarks.

	Hallmarks of Aging
Resveratrol	Genomic instability Telomere attrition  Epigenetic alterations  Loss of proteostasis  Deregulated nutrient-sensing  Mitochondrial dysfunction  Cellular senescence Chronic inflammation  Dysbiosis

• Published in Science, explained resveratrol’s chemoprotective function and later demonstrated that it stimulates sirtuin deacetylase and increases longevity.
• Since resveratrol stimulates sirtuins and blocks mTOR, it is hypothesized to have similar effects on caloric restriction. And nutrient sensing is another hallmark of aging.
• Resveratrol was also shown to be involved in the preservation of genomic stability, both directly and indirectly, as an anticancer agent.
• For telomere shortening, it was studied in a review, and it found that resveratrol’s pro-telomerase effects could protect against the worsening of post-myocardial infarction remodeling.
• In another study, resveratrol’s antiaging effects can be traced back to its ability to reduce oxidative stress, alleviate inflammation, boost mitochondrial activity, and control apoptosis, making it best for cellular senescence.
• Resveratrol also mitigates mitochondrial dysfunction caused by a variety of stimuli. Resveratrol upregulates antioxidant enzymes within mitochondria, hence reducing the formation of reactive species by these organelles.
• Spermidine increases beneficial gut flora and reduces inflammation in studies on animals. Spermidine supplementation improved intestinal barrier function, lowered inflammation, and increased beneficial bacteria in mice.

Resveratrol’s safety, effectiveness, and potential therapeutic activities have been the subject of over 244 clinical human investigations and 27 continuing experiments. It has therapeutic promise against a wide range of disorders, including cancer, diabetes, obesity, hypertension, cardiovascular disease, renal disease, inflammation, Alzheimer’s disease, and more. It has been shown to be safe at dosages up to 5g per day.

3. NMN

The ability of NMN to delay and even reverse the effects of aging was one of the most surprising discoveries of the studies on NMN. (1)(2) NMNsupplementation has been demonstrated to prevent or correct a variety of age-related diseases and hallmarks in clinical and animal tests.

30 or more NMN clinical studies involving human participants are listed on clinicaltrials.org.

Some research, such as in elderly patients treated with NMN for 12 weeks, showed decreased sleepiness and improved leg function.

In another research, improvements in insulin sensitivity were seen in muscle after 10 weeks of NMN compared to placebo, but not in liver or adipose tissue, in a randomized clinical study including 25 obese postmenopausal women.

• In mitochondrial dysfunction, it has been shown to improve mitochondrial bioenergetics, reverse the physiological decline that comes with aging, and stop the breakdown of NAD+ and cell death.
• New research suggests NMN supplementation is associated with anti-atherogenic effects and the enhancement of epigenetic rejuvenation.
• Another research suggests that NMN can increase the longevity-associated activities activated by AMPK, such as improved mitochondrial health and autophagy (the cellular waste disposal system), via raising NAD+ levels.
• A study done on bone tissues suggested that nicotinamide mononucleotide (NMN), a key natural NAD+can be utilized in stem cell regeneration.
• NMN has been found to have the ability to activate sirtuins, a family of proteins that regulate cellular metabolism and nutrient sensing. This can aid in maintaining metabolic balance and preventing age-related metabolic disorders.
• NMN may reduce chronic inflammation, a hallmark of aging. NMN activates sirtuins, aging, and inflammation-regulating proteins. NMN improves immune system function and reduces inflammatory chemicals and enzymes including IL-6, TNF-, and COX-2. This could minimize chronic inflammation and promote healthy aging. (1)(2). 

 

4. CAaKG Calcium Alpha-Ketoglutarate

Like many other supplements, Calcium alpha-ketoglutarate (CAaKG) has also been known to have some longevity-related benefits, and currently, in human studies, the data limits to CAaKG treating 4 hallmarks of aging as yet.

• A randomized, double-blind, placebo-controlled trial published in the journal Nutrition found that AKG supplementation reduced inflammation markers in healthy older adults.
• Calcium AKG inhibits the release of inflammatory substances by senescent cells. (SASP).
• It has also been proven to find have increased cellular response to inflammation (inflammation associated with aging) and reduces the low-grade inflammation associated with the aging process.
• CAaKG supplementation has been found to improve insulin sensitivity and glucose homeostasis in human studies thereby addressing altered cellular communication as a hallmark of aging.

	Hallmarks of Aging
CAaKG	Epigenetic alterations Deregulated nutrient-sensing Altered intercellular communication Chronic inflammation

Human food lacks a source of alpha-ketoglutarate. Although exercise and fasting have been shown to boost AKG synthesis, direct supplementation is the most efficient and practical method for reestablishing normal amounts.

Dr. Sinclair suggests finding a reliable source because it is preferable to ingest AKG that has been refined. Since AKG has been given GRAS classification by the FDA, there is hope that it can be used safely in humans to enhance the lives of the aged.

5. Matcha

It has been found that matcha can reduce 4 out of 12 hallmarks of aging as, 

	Hallmarks of Aging
Matcha Tea	Cellular senescence  Loss of proteostasis Telomere attrition Epigenetic alterations

• Recent research demonstrates that matcha tea polyphenols target 200 human genes, including those implicated in inflammation, cancer, diabetes, neurodegenerative, muscular, and cardiovascular illness.
• Several studies have demonstrated that matcha can prevent liver damage and reduce the chance of developing liver disease by changing the mechanism of loss of proteins.
• Another research suggests that matcha tea is beneficial for telomere lengths of DNA, making it a good use for the anti-aging process. In a review of the matcha green tea component, curcumin, it was found that it provides many benefits to reduce hallmarks of aging telomerase shortening especially.
• Matcha green tea and other high-antioxidant meals have been shown to have anti-aging effects by limiting oxidation, blocking DNA mutation, and repairing damaged DNA.

Modulating gene expression is the underlying biochemical mechanism through which green tea catechins promote the proliferation of new bone-forming cells, reducing the hallmarks of aging.

Improved brain health is also linked to matcha tea drinking, according to a study.

There are antioxidants in matcha tea, but plant compounds also undergo xenohormesis. Molecules like this are produced when plants adapt to harsh environments by producing compounds that alleviate anxiety and delay the effects of aging in humans.

Research is going on in this regard to understand more and more benefits of all of the supplements mentioned above to reverse the hallmarks of aging. There are certainly other drugs/supplements that are specifically helping in reducing the signs and symptoms of aging.

6. Fisetin & Quercetin

Senolytics and senomodifiers are another class of medications in development. These try to eliminate senescent cells or alter their behavior. This will prevent the accumulation of these cells and maybe decrease the physical deterioration associated with aging.

Fisetin is a flavonoid present in a variety of fruits and vegetables, including strawberries, apples, and scallions. In recent years, it has been investigated owing to its potential effects on aging and age-related diseases.

Fisetin, a compound found in plants, has been the subject of numerous anti-aging and longevity-related investigations. By slowing down the aging process and protecting against age-related illnesses, fisetin has the ability to extend life by 10%.

• Supplementing with fisetin decreased inflammatory and cellular senescence indicators in aged mice, according to a 2018 research published in the journal Aging Cell.
• Another research has found that fisetin protects DNA, proteins, and other biological components by removing free radicals.
• Similarly, fisetin has been studied in humans for its anti-oxidative properties and was found to reduce cellular damage and UVB-induced expression.
• In addition to its senolytic properties, fisetin shows promise as a potential tool for preventing the development of cancer cells, slowing cell proliferation, and apoptosis helping with mitochondrial dysfunction.

Quercetin on the other hand is closely related to Fisetin as they both share the same anti-aging properties. Their ability to reverse aging and improve health has been encouraging. Eliminating senescent cells, the final cause of aging, is the molecule’s primary role, suggesting that it may extend life expectancy adding it to the best supplements to reduce the hallmarks of aging.

• Recent research indicates that quercetin may reduce cell senescence by reducing the expression of genes involved in cellular senescence and promoting cell proliferation.
• Quercetin can function as an antioxidant by scavenging reactive oxygen species (ROS) and reducing oxidative stress, thereby protecting mitochondria from damage and enhancing their function.
• Quercetin has been shown to stimulate mitochondrial biogenesis, or the production of new mitochondria by activating key regulators of mitochondrial biogenesis, such as PGC-1α, which can increase the number of functional mitochondria in cells.
• Quercetin can inhibit the production of pro-inflammatory cytokines involved in the development of chronic inflammation, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-). Additionally, quercetin can inhibit the activity of inflammatory enzymes such as cyclooxygenase-2 (COX-2) and lipoxygenase. (LOX).

Hallmarks of Aging  Fisetin Genomic instability Cellular senescence Loss of proteostasis Epigenetic alterations Mitochondrial dysfunction Chronic inflammation Quercetin Genomic instability Cellular senescence Mitochondrial dysfunction Chronic inflammation

Stimulating your longevity genes can also be accomplished by exercising or consuming less food, but above mentioned supplements can also offer a more consistent solution. We propose taking all the supplements according to your choice if you wish to combat the 12 Hallmarks of Aging at once.

It is never too late to make beneficial changes to your daily routine and use natural supplements to assist your body in remaining healthy and strong as you age. Amazing as it may be, the human body may be rejuvenated to some extent if given the proper nourishment. The best anti-aging supplement comprises numerous substances that function on various aging pathways.