Joachim Andersen

Accelerated Learning

The Best Supplements for Increasing Longevity

A distinguished older man with silver hair wearing a brown suit and a patterned tie, standing outdoors with a softly lit background.


In the quest for a longer and healthier life, the science of longevity has shifted its focus from merely extending lifespan to dramatically improving healthspan, the number of years we live in good physical and mental condition. Emerging research highlights a powerful group of evidence-based supplements that may slow biological aging, reduce chronic inflammation, enhance cellular repair, and support metabolic health. From NMN, NR, resveratrol (or berberine), metformin, rapamycin, spermidine, nattokinase, pomegranate, cissus quadrangularis and yerba mate, these compounds target key hallmarks of aging such as mitochondrial dysfunction, senescent cells, and insulin resistance. While no supplement is a magic bullet, the strategic use of the best longevity supplements, backed by rigorous studies, offers a promising tool to help us not only live longer, but thrive well into our later decades.

Table of Content




NAD+ (Nicotinamide Adenine Dinucleotide) is a critical molecule for storing and transferring electrons and is involved in over 500 distinct metabolic reactions in the body. NAD+ is required for every cell of our body to help facilitate energy production. However, NAD+ levels have been observed to wane as we age. Research suggests that by age 50 you have about half as much NAD+ as at age 20. This observation has given rise to the hypothesis that supplementing with NAD+ may help to reverse aging. Adding more fuel to this idea is the fact that DNA damage accumulates with age, and NAD+ plays a vital role in DNA repair. However, because NAD+ is poorly absorbed, oral supplementation is impractical, and the efficacy of intravenous NAD+ injections is questionable. 

As a result, scientists have turned to biochemical precursors of NAD+, nicotinamide riboside (NR) and NMN, which show greater bioavailability and have been proposed to combat aging and extend lifespan by raising NAD+ concentration at the tissue and cell levels. 


Nicotinamide Riboside (NR)

Chemical structure of Nicotinamide Riboside (NR) with labeled elements.


Nicotinamide Riboside (NR) is a form of vitamin B3, known for its role in cellular energy production and as a precursor to NAD+ (Nicotinamide Adenine Dinucleotide). NAD+ is crucial for numerous biological processes, including DNA repair, energy metabolism, and maintaining the health of mitochondria, which are often referred to as the powerhouses of the cell. As such, NR represents a frontier in the quest for longevity and healthspan extension, offering a scientifically-backed approach to enhancing cellular function and potentially mitigating some aspects of aging.

Always consult with healthcare providers before starting any new supplement regimen, especially for those with pre-existing health conditions or on medication.


Benefits and Applications

  • Cellular Energy and Aging
    NR supplementation has been studied for its potential to boost NAD+ levels, which naturally decline with age. This increase in NAD+ might slow down aspects of aging, enhance mitochondrial function, and improve cellular energy production.

  • Cardiovascular Health
    Research suggests that NR could improve heart health by supporting the function of blood vessels and reducing oxidative stress, which is linked to cardiovascular diseases.

  • Neuroprotection
    There’s growing interest in NR for its potential neuroprotective effects, possibly aiding in the prevention or mitigation of neurodegenerative diseases like Alzheimer’s by enhancing neuronal resilience and energy metabolism.

  • Metabolic Health
    NR might help in managing metabolic disorders by improving insulin sensitivity and glucose metabolism, which could be beneficial for conditions like diabetes.

  • Physical Performance
    Some studies indicate that NR might enhance exercise performance by improving muscle mitochondrial function, thereby potentially aiding in endurance and recovery.


Considerations

  • Research Continuity
    While promising, research on NR is still evolving. Long-term effects and optimal dosages for various health conditions are areas of ongoing study.

  • Individual Variability
    Responses to NR can vary. Some might experience benefits in energy levels or cognitive function, while for others, the effects might be less noticeable.





Nicotinamide Mononucleotide (NMN)

Molecule structure diagram showing NR and NMN and precursors to NAD+


Lenney Guarente and a team from MIT incl. Dr. David Sinclair discovered a set of genes that controls aging in yeast cells. What the genes do is that they protect all organism plants, bacteria, humans, etc. from deterioration and disease. Nicotinamide Mononucleotide (NMN) is one of those molecules, so is resveratrol. Among other things, NMN has been shown to lead to faster-growing hair, elevated energy, and appetite reduction.

NMN is a direct precursor to NAD+ (Nicotinamide Adenine Dinucleotide), a coenzyme found in all living cells, crucial for energy metabolism, DNA repair, and maintaining mitochondrial health. As we age, NAD+ levels decline, which is associated with various age-related diseases and the aging process itself. As such, NMN represents a significant area of interest in the field of longevity and healthspan extension, offering a scientifically-backed approach to enhancing cellular function and potentially mitigating some aspects of aging.

Currently, there’s a lack of long-term human studies conclusively proving NMN‘s effect on human lifespan. Most human trials focus on immediate health markers or short-term outcomes. While not directly proving longevity, improvements in NAD+ levels, physical performance, and health markers could theoretically contribute to a longer, healthier life, but this is an inference rather than direct evidence. The field is active, with studies indicating ongoing research into NMN‘s effects on lifespan in mice, which might guide future human studies.

Always consult with healthcare providers before starting any new supplement regimen, especially for those with pre-existing health conditions or on medication.


Benefits and Applications

  • Cellular Energy and Aging
    NMN supplementation aims to boost NAD+ levels, potentially reversing some aspects of aging by enhancing mitochondrial function, improving energy production, and supporting cellular repair mechanisms.

  • Cardiovascular Health
    Research suggests NMN might improve heart health by enhancing the function of blood vessels, reducing oxidative stress, and potentially aiding in the prevention of cardiovascular diseases.

  • Neuroprotection
    There’s growing interest in NMN for its neuroprotective properties. It could help in mitigating neurodegenerative diseases like Alzheimer’s by supporting neuronal energy metabolism and resilience.

  • Metabolic Health
    NMN has shown promise in managing metabolic disorders by improving insulin sensitivity, glucose metabolism, and reducing fat accumulation, which could be beneficial for conditions like diabetes.

  • Muscle Function and Recovery
    Studies indicate NMN might enhance muscle function, aid in muscle recovery, and potentially combat age-related muscle loss (sarcopenia) by improving mitochondrial efficiency in muscle cells.


Considerations

  • Research Continuity
    While promising, research on NMN is still evolving. Long-term effects, optimal dosages for various health conditions, and its direct impact on human longevity are areas of ongoing study.
  • Individual Variability
    Responses to NMN can vary. Some might experience benefits in energy levels or cognitive function, while for others, the effects might be less noticeable.





Resveratrol

Infographic illustrating sources of resveratrol including tangerine, peach, and peanut, alongside health benefits such as antioxidants, cardiovascular protection, anticancer properties, and anti-inflammatory effects.
Image source: MDPI


Resveratrol holds significant promise in the field of longevity science, primarily through its antioxidant, anti-inflammatory and sirtuin-activating properties. You can think of resveratrol as the accelerator pedal for the sirtuin genes, and NMN is the fuel (the gas in the car). Without the fuel, resveratrol will not work. However, translating the above-mentioned benefits from lab studies to practical, safe human applications still requires ongoing research. It would be recommended to take a balanced approach, integrating resveratrol within a broader context of healthy lifestyle choices rather than relying on it as a singular solution for longevity.


Role of Resveratrol

  1. Antioxidant Properties
    Resveratrol acts as an antioxidant, which means it helps neutralize free radicals in the body. Free radicals are unstable molecules that can damage cells, leading to aging and various diseases.

  2. Sirtuin Activation
    Resveratrol is known to activate sirtuins, particularly SIRT1, which are proteins involved in regulating cellular processes like aging, inflammation, and stress resistance. Sirtuins are often referred to as “longevity genes” because they seem to play a role in extending lifespan in various organisms.

  3. Anti-inflammatory Effects
    By modulating various inflammatory pathways, resveratrol can reduce chronic inflammation, which is linked to many age-related diseases like cardiovascular disease, cancer, and neurodegenerative disorders.

  4. Cardiovascular Health
    Resveratrol improves vascular function by promoting vasodilation, reducing blood clotting, and decreasing inflammation in blood vessels, which can lower the risk of heart disease.

  5. Neuroprotection
    There’s evidence suggesting resveratrol can cross the blood-brain barrier, offering neuroprotective effects. This includes reducing oxidative stress in the brain, which could potentially mitigate neurodegenerative diseases like Alzheimer’s.

  6. Cancer Prevention
    While not a cure, resveratrol has shown potential in inhibiting the growth of cancer cells in lab studies. It can induce apoptosis (programmed cell death) in cancer cells and inhibit angiogenesis (the formation of new blood vessels that feed tumors).



Benefits in Longevity

  • Lifespan Extension
    Studies, particularly in lower organisms like yeast, worms, and flies, have shown that resveratrol can extend lifespan. While direct translation to humans is complex, these findings suggest a potential role in human longevity.

  • Healthspan Improvement
    Beyond just extending life, resveratrol might improve “healthspan”, the period of life spent in good health. This is achieved by delaying the onset of age-related diseases, thereby allowing individuals to live more of their life in a healthier state.

  • Metabolic Health
    Resveratrol influences metabolic pathways, potentially improving insulin sensitivity and reducing obesity, which are crucial for preventing diabetes and metabolic syndrome, conditions that significantly impact longevity.

  • Genetic Expression
    It can influence gene expression in ways that mimic the effects of caloric restriction, a well-known method for extending life in many species, without the need to reduce calorie intake drastically.




Metformin

A close-up image of two gold spoons on a black background. One spoon contains several white capsules, while the other spoon holds a mound of white powder.


Research suggests that Metformin may enhance longevity by improving insulin sensitivity, reducing inflammation, and activating pathways like AMPK, which mimic the effects of caloric restriction, a known longevity booster. Its potential to lower the risk of age-related diseases, such as cardiovascular issues and certain cancers, has sparked interest in large-scale studies like the TAME trial, which aims to explore its anti-aging benefits in non-diabetic populations. However, while the data is promising, the need for personalized approaches should is emphasized, as Metformin’s effects can vary based on individual health profiles and should be paired with a nutrient-dense diet and active lifestyle for optimal results.

Close-up of cascading lavender flowers with white tips against a green background.
The French lilac plant (Galega officinalis)
image source


Metformin is derived from the French lilac plant (Galega officinalis), a traditional herbal remedy used for centuries to treat symptoms of diabetes due to its glucose-lowering properties. Scientists isolated and synthesized its active compound, guanidine, in the 1920s, eventually developing the modern pharmaceutical form through chemical modifications to enhance its efficacy and safety.




Rapamycin

Chemical structure illustration of a complex organic molecule, showing various carbon atoms, hydroxyl groups, and nitrogen in a detailed molecular diagram.


Research suggests that rapamycin may enhance longevity by inhibiting the mTOR pathway, a key regulator of cellular growth and aging. This inhibition promotes autophagy, improves protein homeostasis, and reduces inflammation, mimicking some effects of caloric restriction. In animal studies, it has consistently extended lifespan even when started late in life, and it shows potential to delay age-related diseases including cancer, cardiovascular decline, and neurodegenerative conditions. While human data is still emerging, its powerful effects have led to growing interest in low-dose, intermittent use for healthy aging.

The soil bacterium from Easter Island (Streptomyces hygroscopicus)
Rapamycin was discovered in 1965 in soil samples from Easter Island (Rapa Nui). The bacterium Streptomyces hygroscopicus produces it as a natural antifungal compound. Scientists later identified its ability to suppress the immune system and inhibit cell growth, leading to its development as the drug sirolimus (Rapamune). In recent decades, researchers have explored its potential as an anti-aging molecule due to its strong effects on the mTOR pathway.





Spermidine


Research suggests that spermidine may enhance longevity primarily by inducing autophagy, the body’s natural cellular cleanup and recycling process, which declines with age. It also supports mitochondrial function, reduces inflammation, and improves cardiovascular and cognitive health. Large observational studies and animal trials show higher spermidine intake is associated with lower all-cause mortality and protection against age-related diseases. Human trials are still emerging, but the compound is considered one of the most promising natural autophagy inducers. Effects can vary by individual, so spermidine works best when combined with a nutrient-dense diet, regular exercise, and other evidence-based longevity practices.


Wheat germ (Triticum aestivum)
Spermidine is a naturally occurring polyamine found in all living cells. It is especially abundant in wheat germ, soybeans, mushrooms, aged cheese, and certain vegetables. Modern supplements are typically derived from concentrated wheat germ extract, a traditional food source that has been consumed for centuries. Scientists began studying its anti-aging properties in the early 2000s after discovering its ability to trigger autophagy in yeast, leading to the development of standardized extracts for research and supplementation.





Nattokinase


Research suggests that nattokinase may support longevity by promoting healthy blood flow, breaking down fibrin (a protein involved in clot formation), and reducing inflammation and oxidative stress in the cardiovascular system. Its potential to lower the risk of age-related cardiovascular issues, a leading cause of mortality, has generated interest in its role as a natural circulatory supporter. While human data is still emerging, studies indicate benefits for blood pressure regulation and vascular health, making it a promising compound when combined with a nutrient-dense diet, regular exercise, and other evidence-based longevity practices.

Nattokinase is derived from natto, a traditional Japanese fermented soybean dish consumed for over 1 000 years. In the 1980s, Japanese researcher Dr. Hiroyuki Sumi discovered its potent fibrinolytic (clot-breaking) enzyme while screening traditional foods. The enzyme is now extracted and purified from natto for use in supplements, retaining its natural ability to support healthy circulation without the strong taste or texture of natto itself.




Pomegranate


Research suggests that pomegranate may enhance longevity primarily through its rich content of ellagitannins (such as punicalagins), which are converted by gut bacteria into urolithins, particularly Urolithin A. Urolithin A is a potent inducer of mitophagy, the selective recycling of damaged mitochondria, helping to restore cellular energy production, reduce inflammation, and improve muscle function and endurance with age.

Human studies show that Urolithin A supplementation can enhance mitochondrial biomarkers and physical performance in older adults, while pomegranate polyphenols also support cardiovascular health, reduce oxidative stress, and may help protect against age-related cognitive decline.

Although the longevity data is promising and growing, results can vary based on individual microbiome composition, and pomegranate is best used as part of a broader evidence-based longevity strategy that includes a nutrient-dense diet and regular physical activity.


Pomegranate fruit (Punica granatum)
Pomegranate is a fruit native to the Middle East and South Asia that has been used for thousands of years in traditional medicine for its antioxidant and anti-inflammatory properties. Modern research has focused on its ellagitannins, which are metabolized by the gut microbiome into bioactive urolithins. Scientists have isolated and studied these compounds extensively, leading to the development of standardized extracts and the first clinically tested Urolithin A supplement (Mitopure).




Cissus Quadrangularis

Close-up of green vines and small leaves growing over a rocky surface.
cissus quadrangularis
image source


Research suggests that cissus quadrangularis may support healthy aging by promoting bone healing, increasing bone mineral density, reducing joint inflammation and pain, and aiding modest weight management through appetite regulation and fat metabolism improvements. Clinical trials show it can accelerate fracture union and improve mobility in osteoarthritis, while preclinical data indicate potential benefits for metabolic health and preservation of musculoskeletal integrity during aging. Although not as extensively studied for longevity as some pharmaceutical compounds, its traditional Ayurvedic use and modern evidence for bone and joint health make it relevant for maintaining strength, mobility, and metabolic balance in later life. Effects can vary by individual, and it should be paired with resistance training, adequate protein, vitamin D, and a nutrient-dense diet for optimal results.

The Cissus quadrangularis plant
Cissus quadrangularis (also known as Hadjod or Veldt Grape) is a perennial climber native to Africa and Asia. It has been used for centuries in traditional Ayurvedic medicine to promote bone and joint health, accelerate fracture healing, and treat inflammatory conditions due to its rich content of ketosteroids, flavonoids, and other bioactive compounds. Modern standardized extracts are derived from the stems and leaves of the plant.




Yerba Mate

A traditional mate cup made of gourd with a metal straw, surrounded by loose yerba mate leaves and a wooden spoon, placed on a rustic wooden surface.



Research suggests that yerba mate may support longevity by improving metabolic health, enhancing insulin sensitivity, reducing oxidative stress and inflammation, and activating AMPK pathways, mechanisms that overlap with caloric restriction mimetics. Its high content of polyphenols (chlorogenic acids, quercetin, and saponins) has been linked in studies to better cardiovascular health, cognitive function, and potential protection against age-related metabolic decline. While large-scale human longevity trials are still limited, its traditional use and promising preclinical and clinical data have made it a popular natural compound in evidence-based longevity communities.

Ilex paraguariensis (Yerba Mate plant)
Yerba mate is derived from the leaves of the Ilex paraguariensis tree, native to the subtropical regions of South America (primarily Paraguay, Brazil, and Argentina). It has been used for centuries by indigenous Guaraní people as a traditional medicinal and ceremonial tea for its energizing, digestive, and health-promoting properties. Modern science has isolated its key bioactive compounds, leading to growing interest in its role as a natural aid for metabolic and longevity support.




📚 Sources and References



Nicotinamide Riboside (NR)


Nicotinamide Mononucleotide (NMN)


Resveratrol


Metformin




Rapamycin



Spermidine




Nattokinase




Pomegranate



Cissus Quadrangularis




Yerba Mate

Discover more from Joachim Andersen

Subscribe now to keep reading and get access to the full archive.

Continue reading