I’ve been asking the same question for a long time: Why do we age, and can we fight it? This site is my way of chasing the answers and sharing the tools, insights, and science I find along the way.
I’ve been asking the same question for a long time: Why do we age, and can we fight it? This site is my way of chasing the answers and sharing the tools, insights, and science I find along the way.
10 Underrated Longevity Supplements You’ve Never Heard Of (But Should Try in 2025)
Aging is no longer a mystery we simply accept. It is a biological process we can study, and in many ways, influence. Research into longevity supplements shows that certain compounds can protect DNA, restore energy, and calm the inflammation that drives decline.
Most people know the headline anti-aging supplements like NMN or resveratrol. But science has uncovered others that remain underrated, even though they support healthy aging just as powerfully. These hidden compounds strengthen mitochondria, improve cellular repair, and help preserve vitality far beyond the familiar options.
In this guide, we highlight ten of the most overlooked yet effective longevity supplements. They may not be famous, but they target the hallmarks of aging with surprising strength and could be key allies in your strategy for anti-aging and longevity.
Aging is not just about looking older, it is about what happens deep inside our biology. Energy fades as mitochondria lose their spark. DNA repair crews slow down. Inflammation flickers in the background. The scaffolding that holds skin, joints, and vessels strong begins to weaken. Piece by piece, the machinery of life loses efficiency.
Most people turn to the usual names in the longevity world. NMN, resveratrol, omega-3s. They are powerful, but they are not the whole story. Beneath the spotlight, scientists have uncovered compounds that are just as impressive but far less famous. They rarely trend on social media, yet in labs around the world they are showing striking effects on energy, resilience, and cellular repair.
Think of them as the hidden gems of longevity science. Quiet, overlooked, but waiting to be discovered.
How These Supplements Support Healthy Aging
No supplement can freeze time, but some can help us move through it more gracefully. The underrated compounds we are about to explore support the very systems that falter with age.
Calcium alpha-ketoglutarate and creatine fuel mitochondria and keep energy flowing. SIRT6 activator and TMG fine-tune the way genes are expressed, nudging cells back toward youthful function. PEA and hesperidin calm inflammation and protect nerves and vessels, while hyaluronic acid nourishes the matrix that keeps tissues flexible and strong.
Each of these hidden allies works in its own way, but together they point to a simple truth: aging is not fixed, it is flexible. With the right tools, we can nudge our biology toward greater strength, repair, and resilience.
Now let’s explore ten of the most underrated longevity supplements, the ones quietly making waves in research labs and beginning to find their way into the hands of those who want to stay healthier for longer.
How I Chose
I didn’t just throw together a list of popular pills. Each supplement on this page was carefully selected based on how well it aligns with the biology of aging and how strong the science behind it really is.
Category
What I’m looking for
Mechanism relevance
Does it target one or more of the hallmarks of aging in a meaningful way?
Science
How strong is the research? Human trials, mechanistic studies, and consistency with aging pathways
Safety
How well is it tolerated in healthy adults? Are there long-term data or known side effects?
Absorption
Can the body actually use it? Are there delivery methods that improve uptake?
Practicality
Is it easy to find, affordable, and made by reputable sources with clear labeling?
Price guide
I also included a basic cost range, based on average monthly use:
💲 = under $30/month
💲💲 = $30 to $70/month
💲💲💲 = over $70/month
Disclaimer: This is not medical advice. Always consult with your healthcare provider before starting any new supplement, especially if you have underlying health conditions or are taking medications. Some of the links below are affiliate links, which means I may earn a small commission if you decide to purchase through them. It doesn’t cost you anything extra, and it helps support the work I do to research and share longevity science.
My Picks For The Top Underrated 10 Longevity Supplements
• Price: $ $ $ • What it is: SIRT6 Activator is a unique longevity supplement derived from Fucus vesiculosus seaweed, scientifically validated to activate sirtuin 6 (SIRT6), a key longevity gene that controls DNA repair, telomere stability, metabolism, and inflammation. Exclusively offered by DoNotAge, it is the only verified SIRT6 Activator in the world. • Hallmarks Targeted:Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, chronic inflammation.
Average Score:★★★★⯨
✅ Pros
First and only scientifically verified SIRT6 Activator
Targets multiple hallmarks of aging simultaneously
Strong lab validation, trusted by leading longevity researchers
Vegan, allergen-free, high-purity formulation
⛔ Cons
No large-scale human trials yet, most data is preclinical
Premium price compared to standard anti-aging supplements
Exclusively available from one supplier (DoNotAge)
Sirtuin 6 (SIRT6) is a longevity protein that declines with age, reducing the body’s ability to maintain genetic stability and efficient metabolism. By activating SIRT6, this supplement enhances DNA repair, protects telomeres, and supports mitochondrial health. It also regulates glucose and lipid metabolism, improves cognitive resilience, and reduces chronic inflammation at the cellular level.
Hallmark Impact:
DNA damage / genomic instability: Boosts DNA repair enzymes to protect genome integrity
Telomere attrition: Helps preserve telomere length and stability
Mitochondrial dysfunction: Supports metabolic efficiency and energy production
Inflammation: Modulates inflammatory pathways for healthier aging
Epigenetic drift: Maintains youthful gene expression through sirtuin regulation
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★★
★★★★☆
★★★★★
★★★★☆
★★★★☆
Notes
Hits multiple hallmarks of aging directly.
Strong preclinical and mechanistic research, limited human clinical validation so far
Vegan, allergen-free, clean-label with no known major side effects
Liposomal delivery improves uptake, though human bioavailability studies are limited
Easy to take, but premium price and limited availability
Gorbunova, V., & Seluanov, A. (2016). DNA double strand break repair, aging and the chromatin connection. Mutation Research, 788, 2–6.
Mostoslavsky, R., et al. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124(2), 315–329.
Kugel, S., & Mostoslavsky, R. (2014). Chromatin and beyond: The multitasking roles for SIRT6. Trends in Biochemical Sciences, 39(2), 72–81.
Kanfi, Y., et al. (2012). SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell, 11(2), 303–309.
Roichman, A., et al. (2021). SIRT6 activates DNA repair, deacetylates histones, and regulates metabolism. Nature Communications, 12, 6549.
Dzidek, A., Czerwińska‑Ledwig, O., Żychowska, M., Pilch, W., & Piotrowska, A. (2023). The role of increased expression of Sirtuin 6 in the prevention of premature aging pathomechanisms. International Journal of Molecular Sciences, 24(11), 9655. https://doi.org/10.3390/ijms24119655
Reduces inflammatory markers in early human studies
Helps maintain youthful gene regulation
⛔ Cons
Human clinical research is still limited
Benefits may depend on age and baseline health
Works best in sustained-release or calcium-bound form
Ca-AKG feeds mitochondria directly by fueling the Krebs cycle, enhancing ATP production and cellular energy. At the same time, it regulates enzymes tied to DNA repair and epigenetics, helping maintain youthful gene expression.
In animal models, Ca-AKG extended lifespan and improved healthspan by lowering chronic inflammation, supporting stem cells, and improving tissue regeneration. In humans, early studies suggest reductions in inflammatory cytokines and a positive effect on biological age scores.
This makes Ca-AKG not just a metabolic booster but a regulator of cellular health and resilience, a foundation for those interested in anti-aging supplements and life extension strategies.
Hallmark Impact:
Mitochondrial dysfunction: Fuels ATP production in the Krebs cycle
Epigenetic alterations: Modulates demethylase enzymes for youthful gene activity
Nutrient sensing: Influences AMPK and mTOR signaling
Inflammation: Reduces cytokines like IL-6 and TNF-α
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★★
★★★★☆
★★★★★
★★★★☆
★★★★☆
Notes
Targets many key hallmarks keys
Strong animal studies with emerging but still limited human data.
Naturally occurring metabolite with excellent safety profile in supplementation.
Calcium salt form improves stability and uptake, though release form matters.
Available from trusted sources, moderate cost, best in sustained-release capsules.
Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., … & Braas, D. (2014). The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature, 510(7505), 397–401. https://doi.org/10.1038/nature13264
Zhang, J., & Ryu, D. (2020). α-Ketoglutarate: An emerging player in aging and aging-related diseases. Aging Cell, 19(11), e13234. https://doi.org/10.1111/acel.13234
Asadi Shahmirzadi, A., Edgar, D., Liao, C. Y., Hsu, Y. M., Lucanic, M., … & Kapahi, P. (2020). Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metabolism, 32(3), 447–456. https://doi.org/10.1016/j.cmet.2020.07.006
Poon, M. M., Kioh, D. Y., & Pang, Z. (2021). Alpha-ketoglutarate supplementation: Current evidence of benefits for human health. Nutrients, 13(4), 1384. https://doi.org/10.3390/nu13041384
Raj, K., & Horvath, S. (2020). Current perspectives on biological age and the potential role of α-ketoglutarate. Ageing Research Reviews, 62, 101097. https://doi.org/10.1016/j.arr.2020.101097
Gyanwali, B. (2022). Alpha-ketoglutarate dietary supplementation to improve … Trends in Endocrinology & Metabolism. Advance online publication. https://doi.org/10.1016/S1043-2760(21)00266-6
• Price: $ $ • What it is: Hyaluronic Acid (HLA) is a natural glycosaminoglycan found in connective tissues, skin, and joints. It acts as a water-binding molecule that keeps tissues hydrated, flexible, and cushioned. • Hallmarks Targeted:Altered intercellular communication, stem cell exhaustion, and Inflammation
Average Score:★★★★☆
✅ Pros
Maintains skin elasticity and hydration
Supports joint and cartilage health
Enhances extracellular matrix structure
May improve wound healing and tissue regeneration
⛔ Cons
Oral absorption can be variable without advanced delivery
Most research focuses on skin and joints, less on longevity directly
Effects may take weeks to become noticeable
PEA binds to receptors like PPAR-α and indirectly modulates the endocannabinoid system, calming overactive immune responses and reducing inflammatory signaling. This lowers the chronic background inflammation that accelerates biological aging.
It also stabilizes mast cells and glial cells, which are often overactive in chronic pain and neurodegenerative diseases. By reducing their hyperactivity, PEA protects neurons, improves cellular resilience, and promotes better communication between cells.
This makes liposomal PEA a compelling anti-aging supplement, especially for protecting the brain, nerves, and tissues vulnerable to inflammation-driven damage.
Hallmark Impact:
Chronic inflammation: Suppresses pro-inflammatory mediators and mast cell overactivation
Altered intercellular communication: Restores balance in neuro-immune signaling
Loss of proteostasis: Reduces stress on protein-folding machinery by calming inflammation
Neurodegeneration: Protects neurons from inflammatory and oxidative stress
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★☆
★★★☆☆
★★★★★
★★★★☆
★★★★☆
Notes
Strongly targets inflammation and neuroprotection, both central to aging.
Solid human trials for pain and inflammation, fewer direct longevity studies.
Endogenous compound, excellent safety profile, even in long-term use.
Liposomal delivery greatly enhances effectiveness compared to standard PEA.
Increasingly available, though liposomal forms are pricier than standard PEA.
Keppel Hesselink, J. M., de Boer, T., & Witkamp, R. F. (2013). Palmitoylethanolamide: A natural body-own anti-inflammatory agent, effective and safe against pain and inflammation. British Journal of Clinical Pharmacology, 75(5), 908–918. https://doi.org/10.1111/j.1365-2125.2012.04361.x
Skaper, S. D., Facci, L., & Giusti, P. (2014). Mast cells, glia and neuroinflammation: partners in crime? Immunology, 141(3), 314–327. https://doi.org/10.1111/imm.12170
Petrosino, S., & Di Marzo, V. (2017). The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. British Journal of Pharmacology, 174(11), 1349–1365. https://doi.org/10.1111/bph.13580
Gabrielsson, L., Mattsson, S., & Fowler, C. J. (2016). Palmitoylethanolamide for the treatment of pain: Pharmacokinetics, safety and efficacy. British Journal of Clinical Pharmacology, 82(4), 932–942. https://doi.org/10.1111/bcp.13020
Beggiato, S., Tomasini, M. C., & Ferraro, L. (2019). Palmitoylethanolamide (PEA) as a potential therapeutic agent in neurodegenerative disorders. Molecular Neurobiology, 56(1), 232–243. https://doi.org/10.1007/s12035-018-1080-7
• Price: $ $ • What it is: Coenzyme Q10 (CoQ10) is a fat-soluble molecule naturally found in the mitochondria of every cell. It plays a central role in energy production (ATP synthesis) and also acts as a powerful antioxidant. Levels decline with age and are especially low in people taking statins, making supplementation an important strategy for healthy aging. • Hallmarks Targeted:Mitochondrial dysfunction, Loss of proteostasis, Chronic inflammation
Average Score:★★★★⯨
✅ Pros
Enhances energy availability in muscle and brain cells
May protect against age-related muscle loss (sarcopenia)
Supports memory, cognition, and neurological health
Inexpensive and well-studied
⛔ Cons
Can cause mild water retention or bloating in some people
Benefits are more noticeable under high energy demand (exercise, cognitive load)
Long-term longevity-specific effects still under study
Creatine works as an energy buffer, rapidly donating phosphate groups to regenerate ATP during moments of high demand. In aging, ATP production often falters, leading to fatigue, reduced muscle mass, and slower recovery. By maintaining phosphocreatine stores, creatine supplementation helps preserve muscle strength, support mitochondrial efficiency, and even protect neurons from metabolic stress. Recent research also suggests creatine may enhance protein homeostasis and protect against neurodegeneration, making it more than just a sports supplement.
Hallmark Impact:
Mitochondrial dysfunction: Maintains ATP levels when mitochondria are stressed
Loss of proteostasis: Supports protein turnover and muscle maintenance
Strong effect on mitochondrial health and oxidative stress
Backed by decades of mechanistic and clinical research, especially in heart failure and fatigue
Very safe, well tolerated even at higher doses
Variable; improved with oil-based or ubiquinol formulations
Widely available, moderately priced, with multiple trusted brands
Littarru, G. P., & Tiano, L. (2007). Bioenergetic and antioxidant properties of coenzyme Q10: Recent developments. Molecular Biotechnology, 37(1), 31–37.
Shukla, S., et al. (2019). Coenzyme Q10 and its role in aging and neurodegenerative diseases. Current Aging Science, 12(1), 19–25.
Mortensen, S. A., et al. (2014). The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure (Q-SYMBIO trial). JACC: Heart Failure, 2(6), 641–649.
Hernández-Camacho, J. D., et al. (2018). Coenzyme Q10 supplementation in aging and disease. Frontiers in Physiology, 9, 44.
Bhagavan, H. N., & Chopra, R. K. (2006). Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion, 6(3), S66–S72.
Martucci, A., & Nucci, C. (2019). Evidence on neuroprotective properties of coenzyme Q10 in the treatment of glaucoma. Neural Regeneration Research, 14(2), 197–200. https://doi.org/10.4103/1673-5374.244781
• Price: $ $ • What it is: Palmitoylethanolamide (PEA) is a fatty acid amide naturally produced in the body and found in foods like egg yolks, soy, and peanuts. It plays a key role as an endocannabinoid-like molecule, helping regulate inflammation, pain signaling, and nerve protection. • Hallmarks Targeted:Inflammation, Altered intercellular communication, loss of proteostasis
Average Score:★★★★☆
✅ Pros
Strong anti-inflammatory and neuroprotective effects
Supports nerve regeneration and pain relief
Naturally occurring and very safe
Liposomal form improves bioavailability
⛔ Cons
Not as well-known in the longevity field
Human trials mainly focus on pain and inflammation, not direct aging markers
Effects may require consistent use over weeks for noticeable results
Hyaluronic Acid holds up to 1,000 times its weight in water, making it essential for tissue hydration and resilience. With age, natural HLA levels drop sharply, leading to wrinkles, joint stiffness, and weakened barrier function.
Supplementation, especially in liposomal form, improves bioavailability and helps restore extracellular matrix integrity. By supporting hydration and structure in skin, joints, and blood vessels, HLA indirectly reduces chronic inflammation and cellular stress. Emerging studies also suggest a role in modulating stem cell niches, keeping regenerative systems more functional as we age.
This makes HLA not just a beauty molecule but a foundational anti-aging supplement for maintaining youthful tissue function and intercellular signaling.
Hallmark Impact:
Extracellular matrix dysfunction: Restores structural proteins and hydration in connective tissues
Stem cell exhaustion: Supports stem cell niches and regenerative environments
Intercellular communication: Improves signaling between cells via matrix stabilization
Inflammation: Reduces tissue stress and micro-inflammation linked to aging
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★☆
★★★☆☆
★★★★★
★★★★☆
★★★★☆
Notes
Strong impact on extracellular matrix, hydration, and tissue regeneration.
Well-documented for skin and joint health, but fewer direct aging studies.
Naturally occurring molecule, excellent safety profile even at high doses.
Liposomal delivery significantly improves uptake compared to standard oral forms.
Widely available, moderate cost, with liposomal forms being more specialized.
Kawada, C., Yoshida, T., Yoshida, H., Sakamoto, W., Odanaka, W., Sato, T., … & Takahashi, T. (2014). Ingested hyaluronan moisturizes dry skin. Nutrition Journal, 13, 70. https://doi.org/10.1186/1475-2891-13-70
Tashiro, T., Seino, S., Sato, T., Matsuoka, R., & Nakamura, T. (2012). Oral administration of hyaluronan relieves knee pain. Scientific Reports, 2, 232. https://doi.org/10.1038/srep00232
Litwiniuk, M., Krejner, A., Speyrer, M. S., Gauto, A. R., & Grzela, T. (2016). Hyaluronic acid in inflammation and tissue regeneration. Wounds, 28(3), 78–88.
Fraser, J. R., Laurent, T. C., & Laurent, U. B. (1997). Hyaluronan: Its nature, distribution, functions and turnover. Journal of Internal Medicine, 242(1), 27–33. https://doi.org/10.1046/j.1365-2796.1997.00170.x
• Price: $ $ • What it is: Hesperidin is a bioflavonoid found in citrus fruits like oranges and lemons. Traditionally known for supporting blood vessel health and circulation, hesperidin has also been shown to act as a potent antioxidant and anti-inflammatory compound. • Hallmarks Targeted:Inflammation, Altered intercellular communication, Mitochondrial dysfunction, and Genomic instability
Average Score:★★★★☆
✅ Pros
Powerful antioxidant and anti-inflammatory action
Supports blood vessel elasticity and healthy circulation
May protect mitochondria and reduce oxidative stress
Liposomal form improves bioavailability
⛔ Cons
Limited human longevity-specific studies
Most research comes from cardiovascular and metabolic health fields
Can interact with certain medications (anticoagulants, blood pressure drugs)
How it works: Hesperidin works by neutralizing reactive oxygen species (ROS) and lowering oxidative stress, one of the biggest drivers of cellular aging. It also improves endothelial function, keeping blood vessels flexible and reducing the risk of vascular aging.
On a cellular level, hesperidin supports mitochondrial efficiency and modulates inflammatory pathways like NF-κB, lowering the chronic inflammation that fuels biological aging.
Because of its liposomal delivery, hesperidin becomes more bioavailable, allowing it to reach deeper tissues and exert stronger antioxidant effects. This makes it one of the most underrated yet promising anti-aging supplements for cardiovascular resilience, mitochondrial protection, and cellular communication.
Hallmark Impact:
Chronic inflammation: Suppresses pro-inflammatory cytokines and signaling cascades
Mitochondrial dysfunction: Protects mitochondria from oxidative stress, preserves ATP production
Genomic instability: Reduces oxidative DNA damage by scavenging free radicals
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★☆
★★★☆☆
★★★★☆
★★★★☆
★★★★☆
Notes
Strong effects on inflammation, oxidative stress, and vascular aging.
Good preclinical data, some human trials for vascular health, fewer longevity-specific studies.
Generally safe at dietary and supplemental levels; watch for medication interactions.
Liposomal form solves poor bioavailability issue.
Readily available from reputable longevity supplement providers.
Garg, A., Garg, S., Zaneveld, L. J. D., & Singla, A. K. (2001). Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytotherapy Research, 15(8), 655–669. https://doi.org/10.1002/ptr.1074
Roohbakhsh, A., Parhiz, H., Soltani, F., Rezaee, R., & Iranshahi, M. (2015). Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin – A mini-review. Life Sciences, 124, 64–71. https://doi.org/10.1016/j.lfs.2014.12.029
Yamamoto, M., Suzuki, A., Jokura, H., Yamamoto, N., Hase, T., & Shimotoyodome, A. (2013). Hesperidin metabolite hesperetin-7-O-glucuronide improves endothelial function via increased nitric oxide production in human endothelial cells. Journal of Nutritional Biochemistry, 24(2), 360–366. https://doi.org/10.1016/j.jnutbio.2012.07.005
Parhiz, H., Roohbakhsh, A., Soltani, F., Rezaee, R., & Iranshahi, M. (2015). Antioxidant and anti-inflammatory properties of hesperidin and hesperetin: An updated review of their molecular mechanisms and experimental models. Phytotherapy Research, 29(3), 323–331. https://doi.org/10.1002/ptr.5256
Li, Y., Ding, Y., Minireview: Flavonoids and their potential in preventing age-related cardiovascular diseases. Aging and Disease, 12(1), 1–16. https://doi.org/10.14336/AD.2020.0714
Donia, T., Dabbour, N. M., & Loutfy, S. A. (2023). Hesperidin: Advances on Resources, Biosynthesis Pathway, Bioavailability, Bioactivity, and Pharmacology. In J. Xiao (Ed.), Handbook of Dietary Flavonoids (pp. 1–55). Springer, Cham. https://doi.org/10.1007/978-3-030-94753-8_28-1
• Price: $ • What it is: Creatine is a natural compound made from amino acids (arginine, glycine, and methionine) and stored in muscle and brain cells as phosphocreatine. It provides a rapid energy buffer for ATP, especially during high-demand activities. While most people associate it with sports and strength training, creatine is also emerging as a longevity supplement with benefits for cognition, muscle preservation, and cellular energy. • Hallmarks Targeted:Mitochondrial dysfunction, Loss of proteostasis, Stem cell exhaustion
Average Score:★★★★☆
✅ Pros
Restores mitochondrial energy production (ATP)
Strong antioxidant and free radical scavenger
Supports heart, brain, and muscle function
Well-studied, widely available, and generally safe
⛔ Cons
Absorption can be inconsistent, depending on formulation
Best results seen with ubiquinol (active form), which is more expensive
Benefits may be subtle for younger, healthy individuals
How it works: CoQ10 sits inside the mitochondrial electron transport chain, shuttling electrons to generate ATP — the fuel of life. With age, CoQ10 levels fall, weakening energy metabolism and leaving cells vulnerable to oxidative stress. Supplementing restores this vital molecule, improving mitochondrial efficiency, reducing ROS damage, and protecting tissues with high energy demands such as the heart, brain, and skeletal muscles. CoQ10 also contributes to stabilizing cell membranes and modulating inflammatory pathways.
Hallmark Impact:
Mitochondrial dysfunction: Directly fuels electron transport for ATP production
Oxidative stress: Neutralizes free radicals and prevents lipid peroxidation
Loss of proteostasis: Protects proteins from oxidative damage
Inflammation: Helps reduce inflammatory markers, especially in cardiovascular health
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★☆
★★★★☆
★★★★★
★★★☆☆
★★★★★
Notes
Strong energy and muscle-preserving role, with emerging neuroprotective effects
Robust research in sports and clinical contexts; growing evidence in aging and cognitionfatigue
Well tolerated, decades of use with minimal side effects
De Guingand, D. L., Palmer, K. R., & Petersen, A. C. (2020). The emerging role of creatine supplementation in healthy aging and neurodegenerative diseases. Mechanisms of Ageing and Development, 189, 111269. https://doi.org/10.1016/j.mad.2020.111269
Gualano, B., et al. (2012). Creatine supplementation in the elderly: Is resistance training really needed? European Journal of Applied Physiology, 112(5), 1883–1895. https://doi.org/10.1007/s00421-011-2153-6
Avgerinos, K. I., et al. (2018). Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Experimental Gerontology, 108, 166–173. https://doi.org/10.1016/j.exger.2018.04.001
Tarnopolsky, M. A. (2010). Caffeine and creatine use in sport. Annals of Nutrition & Metabolism, 57(s2), 1–8. https://doi.org/10.1159/000322696
Clarke, H., Hickner, R. C., & Ormsbee, M. J. (2021). The potential role of creatine in vascular health. Nutrients, 13(3), 857. https://doi.org/10.3390/nu13030857
• Price: $ • What it is: Berberine is a natural alkaloid extracted from plants like Berberis aristata (tree turmeric) and goldenseal. Traditionally used in Chinese and Ayurvedic medicine, berberine is now gaining recognition as a longevity supplement due to its powerful effects on glucose metabolism, lipid regulation, and mitochondrial health. • Hallmarks Targeted:Chronic inflammation, Mitochondrial dysfunction, Deregulated nutrient sensing, Stem cell exhaustion
Average Score:★★★★☆
✅ Pros
Potent blood sugar and insulin regulator, comparable to metformin
Supports cardiovascular health and cholesterol balance
Shows promise for lifespan extension in animal studies
Anti-inflammatory and antimicrobial properties
⛔ Cons
Absorption is limited; liposomal or combined formulations (e.g., with piperine) are better
May cause mild digestive upset in sensitive users
Long-term human studies in aging are still limited
How it works: Berberine activates AMP-activated protein kinase (AMPK), the body’s central energy sensor. AMPK boosts mitochondrial efficiency, enhances fat metabolism, and improves insulin sensitivity. This makes berberine one of the strongest anti-aging supplements for metabolic health. By improving glucose control and reducing chronic inflammation, berberine reduces risk factors for age-related diseases like diabetes, cardiovascular decline, and neurodegeneration.
Hallmark Impact:
Deregulated nutrient sensing: Berberine restores AMPK activity, improving energy balance and glucose metabolism
Mitochondrial dysfunction: Enhances mitochondrial biogenesis and ATP efficiency
Chronic inflammation: Reduces NF-κB activation and lowers pro-inflammatory cytokines
Stem cell exhaustion: Indirectly preserved by reducing metabolic stress and oxidative damage
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★★
★★★★☆
★★★★☆
★★★☆☆
★★★★☆
Notes
Direct AMPK activation makes it one of the strongest nutrient-sensing modulators
Strong evidence for metabolic and cardiovascular health, growing data in longevity research
Generally safe, but limited long-term safety data for very high doses
Bioavailability is modest unless taken in enhanced formulations
Affordable, widely available, often paired with enhancers like piperine
Turner, N., & Li, J. Y. (2008). Berberine and its derivatives: A novel class of AMPK activators with potential for diabetes and metabolic syndrome. Diabetes, 57(5), 1414–1418. https://doi.org/10.2337/db07-1552
Kong, W., et al. (2004). Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nature Medicine, 10(12), 1344–1351. https://doi.org/10.1038/nm1135
Cicero, A. F., et al. (2020). Berberine for metabolic syndrome: From molecular mechanisms to clinical outcomes. Expert Opinion on Investigational Drugs, 29(9), 989–1000. https://doi.org/10.1080/13543784.2020.1788050
Zhang, H., et al. (2010). Berberine improves glucose metabolism through induction of glycolysis. American Journal of Physiology-Endocrinology and Metabolism, 298(1), E148–E158. https://doi.org/10.1152/ajpendo.00420.2009
Imenshahidi, M., & Hosseinzadeh, H. (2019). Berberine and barberry (Berberis vulgaris): A clinical review. Phytotherapy Research, 33(3), 504–523. https://doi.org/10.1002/ptr.6262
Guo, P., Cai, C., Wu, X., Fan, X., Huang, W., Zhou, J., Wu, Q., Huang, Y., Zhao, W., Zhang, F., Wang, Q., Zhang, Y., & Fang, J. (2019). An insight into the molecular mechanism of berberine towards multiple cancer types through systems pharmacology. Frontiers in Pharmacology, 10, Article 857. https://doi.org/10.3389/fphar.2019.00857
• Price: $ • What it is: EGCG (Epigallocatechin gallate) is the most powerful catechin polyphenol in green tea, accounting for many of its health benefits. It’s widely studied as a longevity supplement for its antioxidant, anti-inflammatory, and metabolic effects. • Hallmarks Targeted:Chronic inflammation, Deregulated nutrient sensing, Cellular senescence, Genomic instability
Average Score:★★★★☆
✅ Pros
Strong antioxidant that neutralizes harmful free radicals
Activates AMPK and supports healthy metabolism
Shown to reduce risk markers for cardiovascular and neurodegenerative diseases
Potential senolytic activity in preclinical studies
⛔ Cons
High doses may cause liver strain in sensitive individuals
Bioavailability is low without specialized formulations (liposomal, phospholipid blends)
Clinical trials on aging are still emerging, most evidence from observational or mechanistic studies
How it works: EGCG protects cells through multiple pathways. As a polyphenol, it directly reduces oxidative stress and prevents DNA damage. It also activates AMPK, improving glucose and lipid metabolism similar to berberine. Importantly, EGCG helps modulate inflammatory pathways and may even encourage the clearance of senescent “zombie” cells, making it a unique anti-aging supplement.
Hallmark Impact:
Oxidative stress: Neutralizes ROS and enhances endogenous antioxidant defenses
Chronic inflammation: Inhibits NF-κB and reduces pro-inflammatory cytokines
Deregulated nutrient sensing: Activates AMPK to restore energy balance
Cellular senescence: Preclinical studies show senolytic-like effects
Genomic instability: Protects DNA from oxidative and chemical damage
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★★☆
★★★★☆
★★★☆☆
★★★☆☆
★★★★☆
Notes
Targets multiple hallmarks including oxidative stress and senescence
Strong preclinical data, growing but limited human clinical trials
Safe in moderate doses; high-dose supplementation may pose liver risks
Bioavailability is modest; enhanced forms improve uptake
Affordable, widely available, often included in green tea extract supplements
Yang, C. S., Wang, H., & Sheridan, Z. P. (2018). Studies on prevention of obesity, metabolic syndrome, diabetes, cardiovascular diseases and cancer by tea. Molecules, 23(3), 528. https://doi.org/10.3390/molecules23030528
Kim, H. S., et al. (2014). Epigallocatechin-3-gallate (EGCG) blocks senescence by modulating p53-p21 pathway in human dermal fibroblasts. Biological & Pharmaceutical Bulletin, 37(9), 1434–1440. https://doi.org/10.1248/bpb.b14-00124
Riegsecker, S., Wiczynski, D., Kaplan, M. J., & Ahmed, S. (2013). Potential benefits of green tea polyphenol EGCG in the prevention and treatment of vascular inflammation in rheumatoid arthritis. Life Sciences, 93(8), 307–312. https://doi.org/10.1016/j.lfs.2013.07.001
Fang, M., Chen, D., & Yang, C. S. (2007). Dietary polyphenols may affect DNA methylation. Journal of Nutrition, 137(1), 223S–228S. https://doi.org/10.1093/jn/137.1.223S
Włodarczyk, M., Ciebiera, M., Nowicka, G., Łoziński, T., Ali, M., & Al-Hendy, A. (2024). Epigallocatechin Gallate for the Treatment of Benign and Malignant Gynecological Diseases—Focus on Epigenetic Mechanisms. Nutrients, 16(4), Article 559. https://doi.org/10.3390/nu16040559
• Price: $ • What it is: TMG (Trimethylglycine), also called betaine, is a naturally occurring compound found in beets, spinach, and whole grains. It acts as a methyl donor, supporting cellular processes like DNA methylation, homocysteine regulation, and liver function. • Hallmarks Targeted:Epigenetic alterations, Mitochondrial dysfunction, Loss of proteostasis, Chronic inflammation
Average Score:★★★★☆
✅ Pros
Supports DNA methylation, an essential epigenetic process tied to healthy gene expression
Works synergistically with NAD⁺ boosters (like NMN or NR) to recycle methyl groups
Affordable and widely available
⛔ Cons
Benefits are indirect compared to more targeted anti-aging supplements
High doses may cause mild digestive discomfort
Limited direct clinical trials in aging, most data from cardiovascular and metabolic studies
How it works: TMG is one of the body’s primary methyl donors, helping transfer methyl groups in reactions that regulate DNA, proteins, and neurotransmitters. As we age, methylation patterns drift (epigenetic alterations), contributing to cellular aging. TMG supports proper methylation, protects DNA stability, and improves liver detoxification. It also assists in recycling NAD⁺ precursors (like NMN) by replenishing methyl groups consumed in their conversion, making it a valuable longevity supplement stack component.
Hallmark Impact:
Epigenetic alterations: Maintains balanced DNA methylation for youthful gene expression
Mitochondrial dysfunction: Supports mitochondrial enzymes and energy metabolism
Loss of proteostasis: Supports protein function via methylation-dependent processes
Category
Mechanism Relevance
Science
Safety
Absorption
Practicality
Score
★★★☆☆
★★★☆☆
★★★★★
★★★★★
★★★★★
Notes
Indirect but important in supporting epigenetic stability and NAD⁺ metabolism
Solid evidence for homocysteine and methylation, limited aging-specific clinical trials
Very safe, widely used, well-tolerated even at higher doses
Excellent oral bioavailability, rapidly taken up and used by cells
Inexpensive, widely available, stacks well with other anti-aging supplements
Schwab, U., Törrönen, A., Toppinen, L., Alfthan, G., Saarinen, M., Aro, A., & Uusitupa, M. (2002). Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. American Journal of Clinical Nutrition, 76(5), 961–967. https://doi.org/10.1093/ajcn/76.5.961
Day, C. R., & Kempson, S. A. (2016). Betaine chemistry, roles, and potential use in liver disease. Biochimica et Biophysica Acta (BBA) – General Subjects, 1860(6), 1098–1106. https://doi.org/10.1016/j.bbagen.2016.02.001
Schwahn, B. C., & Rozen, R. (2001). Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. American Journal of Pharmacogenomics, 1(3), 189–201. https://doi.org/10.2165/00129785-200101030-00005
Konstantinova, S. V., Tell, G. S., Vollset, S. E., Nygård, O., Bleie, Ø., & Ueland, P. M. (2008). Divergent associations of plasma betaine and choline with components of metabolic syndrome in middle age and elderly men and women. Journal of Nutrition, 138(5), 914–920. https://doi.org/10.1093/jn/138.5.914
There is no single best supplement for everyone. The right choice depends on:
Age and health status – younger individuals may focus on NAD⁺ and energy metabolism, while older adults may prioritize mitochondrial or vascular support.
Primary goals – whether the focus is on energy, brain health, inflammation, skin and joints, or metabolic balance.
Lifestyle foundation – diet, sleep, exercise, and stress management are essential before supplementation.
Stack synergy – certain compounds work best in combination, such as NMN with TMG for NAD⁺ metabolism, Berberine with Hesperidin for glucose and vascular health, or Fisetin with Quercetin for senolytic effects.
Example combinations:
Low energy in midlife or older age: NMN, Ca-AKG, and CoQ10
Cardiovascular health concerns: Hesperidin, Berberine, and Omega-3
Brain health and cognition: Creatine, EGCG, and Astaxanthin
DNA repair and epigenetic support: SIRT6 Activator, NMN, and TMG
It is advisable to consult with a healthcare professional before starting or combining multiple supplements.
Frequently Asked Questions
Do these supplements reverse aging? No. They cannot reverse aging, but they may slow the biological processes that drive cellular decline.
Can multiple supplements be taken together? Yes. Many of these compounds are complementary, but it is best to introduce them gradually and monitor personal response, ideally with biomarker tracking.
How long before results are noticeable? Some supplements, such as creatine, PEA, or CoQ10, may provide benefits within weeks, while others, such as Ca-AKG, NMN, or SIRT6 Activator, primarily support long-term cellular health and may take months to show measurable effects.
Takeaway
Aging is inevitable, but the speed and quality of the process can be influenced. These longevity supplements are not magic bullets, yet they are grounded in science and provide meaningful support for cellular resilience, repair, and vitality.
Whether the goal is enhanced energy, healthier aging, or extending healthspan, there is a supplement on this list that can help.
Future reviews will provide deeper analysis of each supplement, including recommended brands, dosage strategies, and guidance for building effective longevity stacks.
The landscape of aging science is changing, and with it, the opportunities to take control of how well we age.