Longevity & Anti-Aging

Fundamentals of a Healthy and Long Life

Nutrition

There is no single miracle diet in terms of longevity. However, scientific data strongly supports dietary patterns that are rich in vegetables, legumes, fruits, nuts, whole grains, quality protein sources, fish, and unsaturated fats such as olive oil, while limiting ultra-processed foods.

The Mediterranean diet is one of the best-researched models in this regard. The randomized PREDIMED study showed that a Mediterranean diet supplemented with olive oil or nuts reduced major cardiovascular events in individuals with high cardiovascular risk [3].

However, healthy eating isn't just about "what we eat." How much we eat is also important, as is whether we're getting enough protein to maintain our body composition, glucose and insulin responses, and muscle mass.

Exercise

The most effective “medicine” in the field of longevity would be if we could put exercise in a capsule. Cardiorespiratory fitness, in particular, has a very strong association with long-term mortality. A large cohort study evaluating more than 122,000 people reported that higher cardiorespiratory capacity was associated with lower all-cause mortality and that there was no clear upper limit to the benefit in the range studied [4].

Therefore, in a longevity program, simply asking "Do you exercise three times a week?" is not enough. VO₂max, muscle strength, muscle mass, balance, and mobility are important components of true functional aging.

A good program should include both aerobic and resistance training. Zone 2 workouts support the aerobic baseline and mitochondrial capacity, while higher-intensity workouts provide a strong stimulus to VO₂max. Resistance training is also crucial for preserving muscle tissue and strength, which we tend to lose with age.

Sleep

Sleep is one of the variables that is sometimes overshadowed by supplements in longevity programs, but is far more important. Insufficient or persistently disrupted sleep has negative effects on metabolic health, appetite regulation, glucose control, immune function, and the cardiovascular system. In meta-analyses of large prospective studies, both chronically short and excessively long sleep durations have been associated with higher mortality [5].

Sleep is not merely a passive period during which the body rests. Deep NREM (slow-wave) sleep, which occurs especially during the night, is an important physiological period during which the brain reorganizes its metabolic homeostasis and increases the removal of metabolic waste products that occur during the day. The brain's glymphatic system plays an important role in this process [16,17].

The glymphatic system is a cleanup system that facilitates the interaction of cerebrospinal fluid with brain tissue through perivascular spaces, contributing to the removal of metabolic waste products. This system is thought to be particularly active during sleep and contribute to the removal of Alzheimer's disease-associated proteins such as amyloid-β and tau [16,17]. More importantly, a human study published in 2026 provided direct human data showing that amyloid-β and tau can be cleared from the brain into circulation via the glymphatic system [18].

Therefore, when evaluating sleep, it is not enough to only look at the question of "how many hours did I sleep?". Staying in bed for seven or eight hours does not mean that quality and restorative sleep was experienced. If sleep is constantly interrupted, the person wakes up repeatedly throughout the night, and does not enter deep sleep sufficiently, the physiological quality of sleep may be low even if the total sleep duration seems normal.

Slow-wave sleep, in particular, appears to be important for glymphatic function. During deep NREM sleep, coordination occurs between slow neuronal oscillations, changes in cerebral blood volume, and movements of cerebrospinal fluid. Current studies suggest that this physiological regulation may be one of the important components of the metabolic cleansing that the brain performs throughout the night [17,19].

What makes this particularly important for Alzheimer's disease is that the relationship between sleep disturbances and neurodegeneration can be bidirectional. Disrupted sleep can negatively impact amyloid and tau clearance; in turn, amyloid and tau accumulation can disrupt the brain's sleep-wake cycle, further worsening sleep quality. This creates a vicious cycle that feeds on each other over time.

Demans hastası olmayan 737 ileri yaştaki bireyin takip edildiği prospektif bir çalışmada, uyku fragmentasyonundaki her 1 standart sapmalık artış Alzheimer hastalığı gelişme riskinde yaklaşık %22 daha yüksek riskile ilişkili bulunmuştur [20]. Daha fazla uyku fragmentasyonu aynı zamanda daha hızlı bilişsel gerilemeyle ilişkiliydi. Bu çalışma nedenselliği kanıtlamasa da, uykunun sürekliliğinin en az toplam uyku süresi kadar önemli olabileceğini göstermektedir.

REM sleep should not be overlooked. Although REM sleep is not considered the primary period of glymphatic cleansing, it is important for memory consolidation, emotional processing, and neural functions. In fact, recent long-term data have shown that both less slow-wave sleep and less REM sleep are associated with greater atrophy in brain regions susceptible to Alzheimer's disease [21].

Therefore, in terms of longevity, restorative sleep is not simply about spending eight hours in bed. The goal is not only to get enough sleep throughout the night, but also for the sleep to be as uninterrupted as possible and for the brain to adequately progress through the different stages of normal sleep architecture, including deep NREM and REM.

If sleep is constantly fragmented, especially due to frequent nighttime awakenings, snoring, sleep apnea, restless legs syndrome, alcohol use, circadian rhythm disorders, or other reasons, it shouldn't be simply interpreted as "I'm sleeping poorly." Chronic sleep fragmentation is a modifiable risk factor for long-term brain health.

Chronic Stress

Our bodies can adapt remarkably well to short-term stress. In fact, our bodies can not only withstand short-term stress; when it is in the right dose and temporary, some stressors can make us biologically more resilient. This mechanism is called hormesis.

Hormesis is the principle that a low or moderate stress factor activates adaptive defense mechanisms in cells, preparing the organism for greater stresses it may encounter in the future. Exercise is a prime example. During intense exercise, temporary oxidative stress, inflammatory signals, and energy stress occur. However, the body responds by strengthening its antioxidant defense systems, mitochondrial adaptation, cellular repair mechanisms, and metabolic capacity. Ultimately, the initial small stress increases the organism's resilience, or biological fortitude.

A similar principle applies to various stimuli outside of exercise, such as sauna and controlled heat stress, cold exposure, energy restriction, and intermittent fasting. Scientific studies show that the temporary stress they create activates cellular stress response and maintenance mechanisms such as AMPK, sirtuins, NRF2, heat-shock proteins, and autophagy, making us more resilient.

The problem is that stress never ends. Chronic psychological and physiological long-term stress creates a constant adaptation cost on the neuroendocrine system, immune system, metabolism and cardiovascular system. Long-term studies have found significant associations between chronic psychosocial stress and telomere shortening, which is one of the indicators of cellular aging [6].

Therefore, stress management is not just superficial advice given "to make you feel good." Sleep, exercise, social relationships, psychological support when needed, and practices that support parasympathetic activity are real components of healthy aging.

Hallmarks of Aging: What Are We Trying to Slow Down?

One of the most important scientific frameworks for longevity research is the Hallmarks of Aging model, which stands for 'Basic Mechanisms of Aging'.

The model, which was introduced in 2013, was expanded in 2023 and today 12 key biological mechanisms associated with aging have been identified [7]. These are:

1. Genomic instability
2. Telomere shortening
3. Epigenetic changes
4. Loss of proteostasis
5. Disruption of autophagy
6. Disruption of food sensing systems
7. Mitochondrial dysfunction
8. Cellular senescence
9. Stem cell depletion
10. Disruption of intercellular communication
11. Chronic inflammation
12. It is a disruption in the gut microbiota.

These mechanisms are not independent of each other. For example, mitochondrial dysfunction can increase oxidative stress and inflammation; chronic inflammation can promote cellular senescence; and senescent cells can affect surrounding tissues through the inflammatory factors they secrete.

Thanks to this model, we now view aging not merely as an inevitable process that occurs with the passage of years, but as a dynamic process whose mechanisms we are increasingly understanding, biologically measurable, and capable of influencing specific components. The biology of aging has progressed far beyond mere experimental curiosity; numerous mechanisms, including metabolic signaling pathways, cellular senescence, epigenetic changes, mitochondrial function, autophagy, and chronic inflammation, can be actively targeted. In the coming period, the combination of artificial intelligence, large biological datasets, multi-omics technologies, and advanced biological age models will allow us to determine much faster and more accurately which interventions are truly effective in which individuals. These developments are not initiating longevity research; rather, they are moving decades of accumulated knowledge in the biology of aging into a much faster era of discovery and personalization.

Further Strategies at Longevity

Once the foundations are optimized, further interventions can be considered based on the individual's needs.

Hormone Optimization

With age, changes occur in many hormonal systems in both women and men, especially in sex hormones. The goal here is not to force hormones back to their peak levels as they were in youth. However, hormonal deficiencies should not be ignored simply by saying they are "a natural consequence of aging."

In women, appropriate hormone therapy around menopause is important not only for symptom control but also for bone health and certain metabolic outcomes. In men, low testosterone should be evaluated in terms of muscle mass, bone, sexual function, and body composition. The goal for longevity is not supraphysiological hormone levels, but maintaining an appropriate physiological hormonal environment for the individual and maximizing their health status.

Optimization of Weight and Metabolic Health

In terms of longevity, not only body weight but also visceral fat amount, insulin sensitivity, lipid metabolism, and muscle-to-fat ratio are important. Obesity is not merely a mechanical weight problem; it is a metabolic condition linked to chronic inflammation, insulin resistance, dyslipidemia, and cardiovascular disease.

Bu nedenle gerektiğinde GLP-1 temelli tedaviler gibi modern farmakolojik araçlar da longevity stratejisinin parçası olabilir. SELECT çalışmasında obez veya fazla kilolu ve mevcut kardiyovasküler hastalığı bulunan, diyabeti olmayan kişilerde semaglutide majör kardiyovasküler olayları yaklaşık %20 azaltmıştır [8]. Bu sonuç, kilo tedavisinin yalnızca estetik bir konu olmadığının çok iyi bir örneğidir.

Sauna, Heat Stress, and Heat-Shock Proteins

Sauna is also one of the interesting areas in longevity research. Exposure of the body to controlled heat stress can trigger the activation of heat-shock proteins (HSPs). These proteins are molecular chaperones that help proteins fold correctly within the cell and are responsible for managing the stress caused by damaged proteins. The fact that the disruption of proteostasis is one of the hallmarks of aging is one of the reasons why heat stress is particularly interesting biologically in this respect [9].

Long-term observational studies conducted in Finland have associated more frequent sauna use with lower sudden cardiac death, cardiovascular mortality and all-cause mortality [10]. In terms of heat adaptation, vascular function, cardiorespiratory stress and proteostasis, sauna is a reasonable and scientifically interesting longevity tool.

Senolytics: Targeting Seninated Cells

Cellular senescence is one of the key hallmarks of aging. These senescent cells, also called zombie cells, are cells that can no longer divide normally but remain metabolically active and can release inflammatory signals to surrounding tissues. We observe that the accumulation of these cells with age contributes to chronic inflammation and tissue dysfunction.

Therefore, senolytics, i.e., molecules that selectively eliminate senescent cells, are one of the most exciting areas of longevity research. The combination of dasatinib + quercetin and fisetin are among the most studied molecules in this field. Early phase studies in humans have shown that dasatinib + quercetin treatment can reduce some biomarkers related to senescent cell load [11].

However, as of today, there is no clinical data directly demonstrating that senolytic therapies extend lifespan in healthy individuals. This presents a significant methodological challenge: considering the length of human life, demonstrating through a classical randomized controlled trial whether an intervention initiated today actually extends lifespan could take decades. Such a study might require 30, 40, or even 50 years of follow-up to see definitive mortality outcomes. Therefore, in longevity research, instead of simply waiting for lifespan, we strive to obtain signals much earlier through indicators of biological age, cellular senescence burden, inflammation, physical capacity, disease-free survival, and other healthspan indicators.

What makes senolytics particularly exciting is the robust biological mechanism behind them. In animal studies, eliminating senescent cells has not only improved certain senescent phenotypes but has also extended healthy lifespan and overall life expectancy in specific models. Initial studies in humans are beginning to show that senolytic approaches such as dasatinib + quercetin can indeed exert a biological effect on senescent cell load and associated biomarkers.

Therefore, saying "we don't know if it works" or "we know it extends human lifespan" regarding senolitics doesn't accurately reflect current scientific knowledge. A more accurate statement would be that this is an area with a strong mechanistic foundation, quite remarkable animal data, and promising early human data, but proving its effect on actual lifespan will take much longer. In fact, we may never see a definitive answer within our own lifetimes as to whether some interventions in the field of longevity actually extend human lifespan. Therefore, using supplements that are found to be safe and not considered risky for humans is sometimes more sensible than waiting for an answer.

Rapamycin and mTOR

Rapamycin is one of the most interesting pharmacological molecules in longevity research. mTOR is one of the key pathways in which cells sense nutrient and growth signals. Reducing mTOR activity can prolong lifespan in many animal models, and therefore rapamycin has become one of the most intensively researched drugs in the field of geroscience.

İnsanlarda henüz “rapamycin ömrü uzatır” diyebileceğimiz veri bulunmamaktadır ama yukarıda da bahsettiğim gibi belki de böyle bir sonuca varmak 30-40 sene sonra mümkün olacakrtır. Bununla birlikte insan çalışmaları giderek daha ilgi çekici hale gelmektedir. Yaşlı yetişkinlerde mTOR inhibisyonunun influenza aşısına verilen immün yanıtı yaklaşık %20 artırdığı ve immunosenesens ile ilişkili bazı göstergeleri iyileştirdiği gösterilmiştir [12].

In the PEARL study published in 2025, healthy aging adults who received low-dose rapamycin weekly for 48 weeks showed no significant increase in serious adverse events; some subgroups showed positive signals in healthspan measures such as lean tissue mass, pain and health perception. However, the study was not large enough or long enough to assess life expectancy [13].

Therefore, rapamycin is a very strong scientific candidate in terms of longevity, but it should still be considered an experimental/off-label geroprotective strategy today.

LDN and Immunomodulation

Conditions such as autoimmune diseases, chronic inflammatory conditions, chronically activated immune systems, and Long COVID, where immune dysregulation may be prominent, can significantly impact a person's overall health and quality of life. The goal in these individuals is not simply to "suppress" the immune system, but to help re-establish a more balanced immune response whenever possible.

Low-dose naltrexone (LDN) is an interesting immunomodulatory tool in this respect. It is thought that low doses of naltrexone can affect neuroinflammation-related mechanisms such as microglial activation and Toll-like receptor-4 (TLR4) signaling, beyond the classic opioid antagonism. Therefore, it is being investigated in conditions such as fibromyalgia, some autoimmune and chronic inflammatory diseases and Long COVID [14].

It wouldn't be accurate to directly consider LDN as a "life-extending drug" here. However, longevity isn't just about how many years we live, but also how healthy those years are. In a select group of patients where chronic inflammation or inappropriate immune activation is prominent, reducing this burden—which can help improve pain, fatigue, functional capacity, and overall quality of life—can provide a meaningful gain in terms of healthspan.

Therefore, LDN's potential place within longevity can be considered not as an anti-aging treatment that should be given to all healthy individuals, but rather as a personalized intervention aimed at reducing this biological burden in the right patient where the immune system and inflammatory response pose a problem.

The world of longevity offers numerous supplements. A significant portion of these make claims far greater than their scientific evidence suggests. However, some molecules are truly fascinating from a biological perspective.

Urolithin AUrolithin A is being investigated as a compound that supports mitophagy, i.e., the clearance of damaged mitochondria. In a randomized controlled trial in middle-aged adults, it was reported that the use of Urolithin A increased some muscle strength measures and produced positive changes in biological markers related to mitochondrial metabolism and mitophagy [15].

Creatine It is not merely a supplement used for sports performance; it is a key component of the phosphocreatine system, which helps meet the rapid energy requirements of both muscle and brain tissue. It is particularly valuable for maintaining muscle mass and strength, especially with aging. Meta-analyses have shown that when used in conjunction with resistance exercise, it can provide additional increases in lean tissue mass and muscle strength in older individuals, beyond the gains provided by exercise alone [16]. Since the brain is also an organ with high energy requirements, the neurological effects of creatine are of particular interest. A recent meta-analysis of randomized studies has reported potential benefits of creatine supplementation, particularly in some cognitive areas such as memory, attention span, and processing speed [17]. Therefore, creatine can be considered one of the best-researched and biologically most sensible nutraceuticals, especially during healthy aging when maintaining muscle reserve and brain energy metabolism becomes crucial.

SulforaphaneSulforaphane is a potent isothiocyanate found in broccoli, and especially broccoli sprouts. Its most interesting feature in terms of longevity is its ability to activate the cell's own antioxidant and cytoprotective defense systems by activating the NRF2 pathway. In addition, it has regulatory effects on NF-κB, inflammasome activation, and inflammatory cytokines [18]. Human data are also not only theoretical: long-term consumption of broccoli sprouts in overweight individuals has been associated with a decrease in inflammatory markers such as IL-6 [19]; other controlled studies in humans have shown that broccoli sprouts rich in sulforaphane can affect oxidative stress and metabolic stress responses.

TA-65, Astragalus membranaceus TA-65 was developed as a telomerase activator and has been investigated particularly in terms of telomere biology. Telomeres are chromosomal structures that tend to shorten with each cell division, and their critical shortening is associated with cellular senescence. In a randomized, double-blind, placebo-controlled human study with TA-65, a significant increase in mean telomere length was reported after 12 months of use, especially in the low-dose group, compared to placebo [20]. A systematic review and meta-analysis published in 2025 also shows that TA-65 creates a positive signal on telomere length [21]. Therefore, although TA-65 is not a supplement proven to prolong human life, it is quite interesting in terms of longevity research because it is one of the few nutraceutical strategies that directly target telomere shortening, one of the fundamental mechanisms of aging.

Low-dose Tadalafil However, in terms of longevity, it targets a completely different mechanism: vascular and endothelial function. By prolonging the effect of nitric oxide–cGMP signaling through PDE-5 inhibition, it promotes relaxation of vascular smooth muscle and blood flow. A study in men with high cardiovascular risk reported that chronic tadalafil use improved endothelial function and that this effect continued for some time even after treatment was discontinued [22]. Improvements in vascular endothelial function have also been reported in other human studies using 5 mg tadalafil daily [23]. Tadalafil, normally given for erectile dysfunction, appears as a supplement that can contribute to vascular health in both women and men at low doses.

Omega-3 fatty acids, magnesium, vitamin D3K2, and multivitamins are also supplements that can be considered essential in many cases. I usually start by recommending these three supplements to most of my patients, and I may use other supplements periodically depending on the goal.

Where to begin?

One of the biggest mistakes in the Longevity approach is starting interventions without understanding a person's current situation. Giving someone supplements, hormones, diets, or exercise protocols without knowing what they truly need is not personalized medicine. The first step is to create a good initial roadmap.

Today, which areas of your health are strong, which are quietly deteriorating, and which can we correct before disease manifests? We cannot manage what we don't measure. Measurement helps us reveal our baseline parameters.

1. Blood and Metabolic Health Profile

Beyond classic blood tests, assessment can reveal a person's cardiometabolic risk in more detail. Fasting glucose and HbA1c, along with fasting insulin and HOMA-IR; standard cholesterol panel alongside ApoB and Lp(a); inflammation markers such as hs-CRP; kidney and liver function tests; and vitamin and mineral status are important components of the baseline profile. The aim is to identify potential future problems before disease develops and to intervene in those that are truly modifiable.

2. Body Composition

The weight shown on the scale is not sufficient for longevity. Two people may weigh the same, but one may have high muscle mass and low visceral fat, while the other has low muscle mass and high visceral fat. Therefore, DEXA or reliable body composition analyses are extremely valuable, especially in terms of muscle mass, fat distribution, and visceral adiposity. The goal for a long life is not simply to be "thin," but to remain metabolically healthy and muscular.

3. VO₂max and Physical Capacity

Given the relationship between cardiorespiratory fitness and mortality, VO₂max is one of the most valuable functional measures in longevity assessment. Higher cardiorespiratory capacity is strongly associated with long-term survival [4]. VO₂max provides us with a holistic performance measure that shows not only how your heart works, but also how efficiently the heart, lungs, vascular system, muscle tissue and mitochondria work together. Tracking the development of this value over time is a very valuable indicator.

4. Hormone Profile

Assessing thyroid hormones, testosterone, estradiol, progesterone, DHEA-S, SHBG, LH, FSH, and other hormones according to age, gender, and clinical presentation can provide a starting point for understanding hormonal health. Understanding how hormones relate to a person's muscle mass, bone health, metabolism, energy, sleep, libido, and overall function is crucial. In addition to blood hormone levels, evaluating steroid hormone metabolites can provide more detailed information about how hormones are metabolized.

5. Functional and Metabolic Tests

A more detailed longevity assessment may utilize different tests depending on the individual. Further functional tests, such as those measuring organic acids, amino acid metabolism, oxidative stress markers, metabolites associated with mitochondrial energy production, or hormone metabolites, also help in planning the appropriate supplements for each individual.

The True Power of Longevity: Measure – Intervene – Measure Again It is based on the principle that knowing what improvements the changes and interventions have brought to a person's health status is very valuable.

The real power lies in measuring a person's health status as objectively as possible, identifying their weaknesses, prioritizing interventions that will yield the greatest return, and then measuring again whether they are actually working.

Perhaps your glucose levels are normal, but your insulin levels are steadily rising.

Perhaps your weight is normal, but you have excess visceral fat.

Your cholesterol may appear "normal," but your ApoB or Lp(a) levels may indicate a high risk.

Perhaps you exercise regularly, but your VO₂max level is lower than you would expect for your age.

You may feel healthy, but your muscle mass has decreased significantly in the last five years.

Treating a disease after it has developed is not the same as trying to change the direction of risk years before a disease occurs. In my opinion, this is precisely the most valuable aspect of the longevity approach. Create a starting point for your health.

The first step is to accurately assess where you are today. A comprehensive blood and metabolic evaluation, body composition, cardiovascular risk analysis, VO₂max, hormonal assessment, and, if necessary, further metabolic tests can create a current health profile. Based on these results, areas of real need are identified, and personalized plans can be developed for nutrition, exercise, sleep, weight management, hormones, or further longevity treatments.