THE BATTLE AGAINST AGING

George Burns said, “You can't help getting older, but you don't have to get old.”

?

Wear and tear of the genetic code over the years is considered to be the main cause of aging. Biological aging is a universal biological process, a natural phase in the life cycle of each individual, which ends in death.

?

Human life expectancy is influenced by many factors such as genetics, lifestyle, living conditions, working conditions, and the human relationship to health.

?

Although we cannot influence genetics, nor the environment that affects us, we can adapt our lives and behavior to the conditions and prolong the lifespan.

?

Some people may look old by appearance, behavior, and attitude as early as 30 years of age, while others even at the age of 60 act and look as if they are much younger. In youth, one should think about how to cope with aging and preserve one's work and health abilities for later years. A tidy life, proper and regular diet, and regular visits to the doctor are just some of the prerequisites for longer life. We can preserve our health with regular care, proper nutrition (with plenty of fruits, vegetables, and fluids), moderate physical activity, and staying outdoors while avoiding excessive exposure to sunlight.

?

A healthy diet and supplementation with anti-oxidents and other chemicals can substantially slow the aging process allowing for a longer period of health (health span) while also increasing the length of life.

?

The purpose of this article is to explore how we age, why we age and how to extend both the health span and age span.

?

WHAT HAPPENS AS WE AGE

?

Aging is a natural, time-dependent process characterized by the progressive appearance of irreversible changes in cells, tissues and organs. Aging is characterized by permanent loss of proliferative capacity, reduction of tissues and physiological functions?and increased susceptibility to disease. During aging, there is a progressive decrease in the volume of intracellular fluid, reduced ability to eliminate toxins, reduced metabolism, reduced blood flow to organs (due to pronounced sclerotic changes in blood vessels)?as well as more frequent neoplasms. Locomotor abilities of a person reach their culmination around the age of thirty, in the 50th year a person has 70% of maximum physical abilities, and in the 70th with only 55%. With age, a person loses height, muscle mass, and total weight ibid. Weight decreases due to loss of lean mass, water, and bone mass (reduction of cell mass by 64% after age 70) Id.. Changes in the cardiovascular system include decreased heart rate, increased end-diastolic volume, decreased sensitivity to catecholamines, diastolic dysfunction, and decreased myofibril contractility. In addition, respiratory dysfunction occurs, residual volume increases, parenchymal elasticity decreases, pulmonary compliance increases, so as the risk of atelectasis (collapse of one or more areas in the lung). Atrophy and reduction of neurogenesis appear in the nervous system, especially in the hippocampal region. Hearing loss also develops, especially for high frequencies, as well as an impaired sense of taste for salty and bitter (less affected sense of sweet and sour), senile hyperopia, and often cataracts. Endocrine glands go through structural and volume changes. Insulin requirements substantially increase and can double. Due to a decrease in the number of receptors and damage to the post-receptor signaling pathway, there is a reduced sensitivity to the action of growth factors and hormones. Aging is also characterized by loss of reproductive ability, a decline in sexual tension and activity, as well as profound emotional changes. Psychologically, aging is characterized by changes in the mental sphere, which often represent a source of conflict with the environment, leading to alienation from work, intrapersonal conflicts, and disturbed family relationships. Organic psychosis?(senile and presenile dementia, bipolar psychosis, atherosclerotic dementia, paranoia), neurotic disorders, and psychosomatic diseases are more common in the elderly. Neurotic disorders include anxiety, hysteria, and narrowing of consciousness, phobias, neurotic depression (fatigue, headaches), hypochondria, and anorexia. The most common psychosomatic diseases are ulcer disease, some forms of asthma and allergies.

Aging is accompanied with different aging-related diseases:

?

-?Cardiovascular disease

-?Hypertension

-?Cancer

-?Diabetes

-?Osteoarthritis

-?Osteoporosis

-?Multiple chronic conditions

WHY WE AGE

?

Scientific data indicate that aging and death are the result of numerous interactions at the genetic level and influences from the external environment. Bearing in mind that the length and quality of our lives depend on two components, heritage and environmental factors, the question of the individual share of each of them arises. Studies with monozygotic twins have shown that hereditary factors are responsible for only 1/3, and environmental factors for the other 2/3 of life expectancy variations. Thus, the pronounced heterogeneity in the aging of individuals is the result of differences in genetic system, living conditions and lifestyle, and random variations. Another unanswered question is why eukaryotes age and die. So far, more than 300 theories of aging have appeared in the literature. Numerous theories do not have to be mutually exclusive, but many overlap and complement each other. Moreover, due to the extreme complexity of the aging process, it is unlikely that there is only one mechanism responsible for the onset of aging, which is universal for all animals. Id.

?

THE ROLE OF FREE RADICALS IN THE AGING PROCESS

?

Damage caused by free radicals is believed to be the main cause of tissue aging, but also a key factor for the development of many degenerative diseases, such as atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer's disease, and diabetes. In 1956, Harman was the first to argue that degenerative diseases associated with aging represent side effects of free radicals on cellular elements and that antioxidants protect against the oxidative damage they cause. ?The content of antioxidants in cells decreases with aging. Being unstable and highly reactive molecules, free radicals can induce chain chemical reactions in which new free radicals are formed, leading to damage of all cellular structures. Free radicals include reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS includes superoxide anion (?O2-), hydrogen peroxide (H2O2), peroxyl radical (ROO?) and hydroxyl radical (HO?), while RNS includes nitric oxide (NO?) and peroxynitrite anion (ONOO-). ROS and RNS are formed as products of normal cellular metabolism and, depending on the concentration in the cell, can have a beneficial or harmful effect. Under normal physiological conditions, ROS and RNS are present in low concentrations, are involved in numerous signaling processes in the cell, regulate gene expression and cell growth, protect against various infectious agents and trigger a mitogenic response. In large quantities, either due to their excessive production (or increased amount of exogenous free radicals, such as from air and water pollution, smoking, alcohol, drugs, etc.) or due to disruption of the antioxidant protection system, free radicals cause oxidative damage to lipids, proteins, and DNA molecules, which leads to numerous pathological conditions in the body and accelerates the aging process. Polyunsaturated fatty acids (PUFAs, fatty acids that contain more than one double bond in their backbone) are more prone to oxidative damage than other macromolecules in the cell, and sensitivity to radicals increases exponentially with an increasing number of double bonds. Oxidation of polyunsaturated fatty acids of the cell membrane (lipid peroxidation) results in increased membrane permeability, the appearance of rigidity, and dysfunction - which is the basis of the membrane theory of aging.

?

To cope with the deleterious effects of oxidative stress, the living organism has created a very complex antioxidant defense system. Under physiological conditions, there is a balance between the oxidation process caused by free radicals (oxidants) and the antioxidant defense system. While the young organism possesses an adequate amount of antioxidants and enough energy to regenerate cellular macromolecules, in the elderly the ability to protect against damage caused by free radicals is weakened and the regeneration process is much slower. The antioxidant defense system consists of molecules capable of interacting with free radicals and reducing their amount in our body. These molecules are electron donors, which convert radicals into stable, non-toxic metabolites. The antioxidant system contains enzymatic and non-enzymatic antioxidants. The main antioxidant enzymes are superoxide dismutase (SOD), glutathione peroxidase (selenium-dependent and selenium independent forms), and catalase. The main non-enzymatic antioxidants in biological systems are Vitamin E, Ascorbic acid (Vitamin C), β-carotene, cysteine, glutathione, coenzyme Q10. Coenzyme Q10 (CoQ10), also known as ubiquinone, is an essential component of the mitochondrial respiratory chain and is an important element in the body's defense against superoxide radicals. With age, the amount of CoQ10 in the body decreases, so that a person aged 80 years has half the amount of CoQ10 in the heart, lungs, and spleen than in a 20-year-old.

?

MITOCHONDRIAL THEORY OF AGING

?

Mitochondria are rod-shaped cell organelles, about 1 μm long, with a double membrane and their own DNA. Namely, each mitochondria contains 4-5 copies of its own circular DNA. Mitochondria are extremely important cellular organelles, because they provide about 90% of the energy needed for the body to function. The number of mitochondria in a cell depends on the activity of the cell and its energy needs. Therefore, more mitochondria are found in cells that show a high degree of metabolic activity, such as neurons and muscle cells, in which mitochondria make up about 40% of the cell volume. In mitochondria, energy is created by the process of aerobic respiration, in the form of adenosine-tri-phosphate (ATP) molecules. Mitochondria are not only the main source of energy for most eukaryotic cells, but also the main source of free radicals. 90% of free radicals are produced in mitochondria. In 1972, Harman and his coworkers presented the mitochondrial theory of aging. The mitochondrial theory of aging is based on the long-term accumulation of somatic, mitochondrial DNA (mtDNA) mutations. Damage to mtDNA can be multifactorial, which results in impaired cellular integrity and functionality, apoptosis and aging. Mitochondrial dNA mutations occur 10 - 20 times more often than nuclear DNA mutations. Unlike nuclear DNA, mitochondrial DNA does not have a protective histone protein, and the repair of genetic defects in mitochondria is less efficient. Mitochodnrial ROS disrupts the further transport of electrons and reduces the amount of created ATP. In addition, induction of the apoptosis process can occur, because mitochondria play an important role in regulating this process (by releasing cytochrome-c from the mitochondria into the cytoplasm and activating the enzyme caspase). Aging is also associated with increased production of superoxide, which can damage the inner membrane of mitochondria and induce further production of superoxide. There is no doubt that DNA damage contributes to the further progression of aging, given that these are changes in the central control system, on the basis of which each cell functions and reproduces, and which controls its behavior.

?

TELOMERE SHORTENING

?

Telomeres are short repeated nucleotide sequences at the end of the eukaryotic chromosome, which protect the chromosome from degradation by enzymes called exonucleases. In the absence of telomeres, chromosome fusion and massive genetic instability occur. Telomeres protect chromosomes in two ways: they are a reservoir of non-coding DNA sequences (sequence of DNA that do not code amino acids) and bind proteins that prevent degradation of chromosome ends. Telomeres are thought to play the role of a "clock" that regulates the cell cycle and limits cell division capacity. Telomere shortening is a molecular mechanism that controls the time and number of cell divisions, and aging occurs in response to the presence of permanently shortened telomeres. During each cell division, telomeres shorten by 50 to 100 terminal nucleotides due to the inability of DNA polymerase to replicate the terminal portion of the chromosome. Complete loss of telomeres, is called a terminal deletion and results in the formation of ring chromosomes. Telomere length is thought to be genetically determined, and is 7000 to 10000 nucleotides. Stabilization of telomeres is achieved by the action of ribonucleoprotein enzymes - telomerases, which increase the length of telomeres at the ends of chromosomes by adding hexameric repeats. High telomerase activity exists in germ cells, stem cells, epidermal skin cells, hair follicle cells, as well as in malignantly altered cells. The telomerase system is characterized by functioning on the "on-off" principle, so many cells, although they have these enzymes, enter the process of premature aging due to their non-functionality (permanent "off" stage). Malignantly altered cells (permanently active telomerases) have the ability to produce continuously, which makes them immortal. Many experiments have shown a direct association of telomeres with the aging process, as well as the ability of telomerases to prolong life by increasing the number of cell divisions. Telomerase activity decreases with age.

?

CELLULAR SENESCENCE

?

Cellular senescence is defined as a condition in which a cell’s ability to multiply has been lost. Senescent cells are metabolically active but are permanently stopped in the G1 phase of the cell cycle and do not respond to external stimuli. Several cellular stressors, such as oxidative stress and telomere disruption, can cause cellular senescence. Senescent cells can be found in old or damaged tissues, and they can impair tissue regeneration capacity as people get older. Older cells are more common in stress-prone tissues, such as lower extremity veins, blood vessels, prostate, bones, joints and skin. An aging cell has two or three characteristics that together define its phenotype: 1) basically irreversible cessation of proliferation, 2) insensitivity to apoptosis-inducing signals in some cell types, and 3) changes in differentiated cell functions

?

Cessation of proliferation.

?

Irreversible cessation of division is the most striking feature of an aged cell. It is a consequence of repression of genes necessary for cell cycle development and increased expression of genes that inhibit cell cycle development. Stopping division, as an undoubted sign of cell aging, could be responsible for the weakening of nerve functions, hematopoiesis and the development of diabetes during aging. Thus, cell aging could contribute to overall aging by preventing stem cell or precursor cell proliferation.

?

Insensitivity to apoptosis.

?

Apoptosis or programmed cell death is a response to physiological signals, stress and damage, which in a precisely controlled way eliminates unnecessary, dysfunctional or potentially malignant cells from the tissue. Like cellular age, apoptosis is a protective mechanism against the development of malignant tumors in youth. During aging, however, some mitotically active cells (human fibroblasts, T cells, mammary gland epithelial cells) become insensitive to stimuli that normally cause apoptosis, accumulate, and increase the number of damaged and dysfunctional cells in tissues. On the other hand, the potentially harmful effects of cell death during aging are most evident in postmitotic tissues, where cells are difficult to regenerate. In some parts of the brain and in skeletal muscle, cells can be compensated by the mobilization of stem or precursor cells, but it seems that these cells also have a finite lifespan and their number decreases with age. Both apoptosis and necrosis, as other type of cell death, can intensify during aging due to an increase in oxidative or some other type of damage and lead to depletion of cell reserves to a degree that results in atrophy or degeneration.

?

Functional changes.

?

As cells age, their functions change, including increased secretion of molecules that can have a detrimental effect on the tissues’ structure and integrity. Older cells can secrete proteases, proinflammatory cytokines (IL-1), tumor necrosis factor (TNF) and growth factors. Proteases directly, and other molecules indirectly, by stimulating inflammation, damage tissue structures. Growth factors can disrupt proliferative homeostasis and even stimulate the growth of mutated preneoplastic or neoplastic cells.

?

FIGHTING THE INTERNAL CLOCK

?

While there are many mysteries surrounding aging and the mechanisms that cause it, one thing is for sure – we can’t stop the internal clock from ticking. But we can fight against it and slow it down. Proper nutrition and regular exercise are a prerequisite for long life, while the addition of certain supplements can significantly improve our health.

?

Having in mind the role of oxidative stress in aging, antioxidant supplementation can have significant therapeutic effects. Vitamins B (B6, B9, B12), D, and K, and alpha-lipoic acid?are some of the most studied antioxidants with anti-aging properties. Vitamin B deficiency is frequent among the elderly, and it has been linked to an increased risk of age-related disorders. B-vitamins are required for DNA synthesis and stability. Therefore it is not a surprise that Vitamin B, either alone or in combination with other supplements, is often used in clinical studies related to aging. Controlling the growing burden of dementia is getting increasingly challenging as the world's population ages. This is particularly true in the case of Alzheimer's disease (AD), the most frequent form of dementia in the elderly, and Vitamin B9 (folic acid) was shown to improve cognitive capacity in people with AD.

?

Skin health, although obvious as a sign of aging is often not considered as important and yet the skin is to act as a barrier against insults from the environment, thus its appearance generally reflects the health and efficacy of its underlying structures. Normal skin contains high concentrations of vitamin C (time release?supplementation is often the best as too much ascorbic acid can have a deleterious effect on the gastrointestinal system), which supports important and well-known functions, stimulating collagen synthesis and assisting in antioxidant protection against UV-induced photodamage. Adequate vitamin C intake is also critical in the slowing the onset and progression of Alzheimer’s disease and is an anti-oxidant.

?

The endogenous antioxidant system can be boosted by dietary supplementation with essential minerals, such as magnesium, zinc, copper, chromium, selenium. Zinc and copper, among others, are found in the catalytic (active) center of copper-zinc superoxide dismutase, an antioxidant enzyme involved in the neutralization of superoxide. Selenium is found in selenium-dependent glutathione peroxidase, whose main role is the neutralization of hydrogen- and other organic peroxides, thus involved in oxidative defense mechanisms. In combination with Coenzyme Q10, selenium can reduce cardiac fibrosis. This is of great importance since part of the aging process in the cardiovascular system involves fibrogenic activity, characterized by an increased synthesis of collagen. Through the increased amount of collagen in the myocardium, the normal architecture of the myocardial wall gradually becomes changed, which increases the risk of developing into different cardiac disturbances and eventually heart failure and death.

?

Moreover, supplementation with amino acids (building blocks of proteins) or their derivatives, such as arginine, cysteine, alanine, and ornithine oxoglutarate (ornithine ketoglutarate), was shown to have protective effects for the elderly population.

Many naturally occurring antioxidants are used for aging treatment. Curcumin, melatonin?(only can be taken at night), and resveratrol?are among them and are commercially available as supplements. Curcumin is produced by plants of the Curcuma longa species, while resveratrol can be found in the skin of grapes, blueberries, raspberries, mulberries, and peanuts. MitoQ, a mitochondria-targeted antioxidant made up of ubiquinol, a naturally occurring antioxidant, and a lipophilic cation, is another promising anti-aging supplement used for treating age-related vascular dysfunction.

?

Scientific data points to the beneficial effects of using mixed compounds and whole extracts due to additive and synergistic relationships of individual chemicals present in the mixture. In terms of aging, several plant extracts and mixtures showed beneficial effects in elderly people.

?

Aging is often accompanied by declines in cognitive function, leading to lower quality of life and increased need for care among older adults. Diets rich in fruits and vegetables can reduce the risk of age-related cognitive impairment. Several studies provided results for improvement in cognitive performance after daily blueberries consumption. Lifestyle factors, including diet, have a great impact on endothelial function as well. Endothelial is a thin membrane that lines the inside of the heart and blood vessels and has several important functions, including blood vessel formation, coagulation, and fibrinolysis, regulation of vascular tone, or role in inflammation. Endothelial dysfunction is a primary mechanism involved in the development of arteriosclerotic disease and represents a significant predictor of cardiovascular risk. The consumption of diets rich in monounsaturated fatty acids (MUFAs) has been linked to improved endothelial function. One of the most studied MUFA-rich diets is the Mediterranean diet (with a focus on olive oil?as a good fat), recommended as the alternative for unhealthy Western diet, rich in saturated fatty acids and processed carbohydrates.

?

The induction of autophagy was proven to be a successful approach for anti-aging therapy. Autophagy upregulation is also a common feature of lifestyle interventions that slow down aging (i.e. dietary (caloric) restriction, exercise) and of drugs and natural products (generically known as geroprotectors) that improve lifespan. Geroprotectors proved to upregulate autophagy and benefit health span and lifespan include rapamycin and its analogs, spermidine, resveratrol, nicotinamide adenine dinucleotide (NAD+), etc.

?

Caloric restriction (CR) is another strategy for improving longevity and attenuating the age-related increase in chronic disease risk. CR is defined as a reduction in energy intake below the amount that would be normally consumed while maintaining an adequate intake of essential nutrients. CR mimetics such as sirolimus, to a lesser degree tacrolimus?and their ilk taken in low doses on a weekly basis (4-6 mg once a week is considered most efficacious though trough levels for standard rapamycin dosing in humans is 3–20 ng/ml)?acting to limit the Mtorc1 pathway has been shown to be both a good senolytic agent (autophagy) as well as a method to prevent neoplasms. (us of 1% sirolimus crème?over a long period has been shown to produce autophagy on the epidermis thus eliminating wrinkles and other age related physical signs as well as increasing elasticity.)

?

Targeting fundamental mechanisms of aging has the potential to reduce the severity of multiple age-related diseases. Being one of the key mechanisms that drive age-related diseases, cellular senescence is a potentially great therapeutical target. Senolytic agents (Dasatinib and Quercetin) are drugs that selectively induce apoptosis (autophagy) of the senescent cell. Spermidine (found in wheat germ) has also been shown to induce apoptosis. These agents were shown to decrease senescent cells and improve physical function in humans.

?

Key pathologies of aging, including oxidative stress, mitochondrial malfunction, and the associated mTOR, AMPK and NAD+ signaling pathways have been verified to be regulated by Chinese herb rhizoma coptidis (RC) components (RC is composed of diverse alkaloids, including berberine (6.88% to 13.64%), palmatine (1.28% to 2.12%), jatrorrhizine (0.77% to 1.32%), coptisine (0.42% to 0.85%), and epiberberine (0.42% to 0.92%), with berberine being the primary compound), especially berberine. RC and its main bioactive components have attracted attention in recent years owing to its wide spectrum of pharmacological effects, particularly in aging-related diseases, including that against hypertension, hyperglycemia, hyperlipidemia, cancer, arrhythmia, depression, etc.

?

Metformin?has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus. Berberine?was an ancient herbal medicine in treating diarrhea. Metformin and Berberine regulate glucose and lipid homeostasis as well as limit cancer growth and inflammation and thus both are used to treat diabetes, assist with obesity, cardiac disease, tumors and inflammation.

?

Above mentioned treatments and strategies for combat aging, and some others, with dosage and observed effects, are presented in the following pages.

?

?Good references:

?

?

https://age-reversal.net/

Treatment

Dosage

Effects

Reference

Vitamin B addition to Vitamin D and calcium supplementation

1200 IE vitamin D3, 800 mg Ca-carbonate, 0.5 g folic acid (Vitamin B9), 50 mg Vitamin B6, and 0.5 mg Vitamin B12. VitB capsules taken in the morning, VitD+Ca taken as two capsules (1 at midday and 1 in the evening) just after the meal, for 12 months

Using B-vitamins in addition to vitamin D+Ca in the elderly was associated with lower biological age

(Obeid et al., 2018)

Folic acid + Vitamin B12 + Vitamin B6 + Calcium + Vitamin D

500 μg of folic acid, 500 μg of B12, 50 mg of B6, 456 mg of Ca, and 1200 IU of vitamin D daily for 12 months.

An active role of supplementation with these vitamins for the maintenance of genome stability was suggested

(Pusceddu et al., 2017)

Folic acid (Vit B9)

5 mg daily for 6 weeks

Chronic folic acid treatment boosted vasodilator function in healthy aged skin, implicating improved vascular endothelial function in older adulthood.

(Stanhewicz et al., 2015)

Folic Acid

1.25 mg daily, during or immediately after a meal, for 6 months

Folic acid improved cognition and markers of inflammation in newly diagnosed patients with Alzheimer’s disease

(Chen et al., 2016)

Folic Acid

daily oral dose of one tablet consisting of 400 μg folic acid

Folic acid supplementation improved cognitive function among people with mild cognitive impairment

(Ma et al., 2016)

Folic acid + Vitamin B12

two tablets of 400 μg folic acid plus one tablet with 25 μg vitamin B12 daily for six months

Improved cognitive performance and decrease the levels of inflammatory cytokines in peripheral blood of elderly people with mild cognitive impairment

(Ma et al., 2019)

Folic acid + Vitamin B12

400 μg folic acid plus 500 μg Vitamin B12 daily for 2 years

Supplementation with folic acid + vitamin B12 can induce epigenetic changes in the DNA and possibly prevent the development of the diseases

(Sae-Lee et al., 2018)

Vitamin K

Daily supplementation with 500 μg phylloquinone along with multivitamin (thiamine (1.6 mg), riboflavin (1.8 mg), vitamin B-6 (2.1 mg), vitamin B-12 (3 μg), vitamin C (75 mg), vitamin E (12 mg), pantothenic acid (6 mg), niacin (20 mg), folate (160 μg), and biotin (30 μg)), 600 mg calcium and 400 IU Vitamin D

Vitamin K supplementation reduced the progression of existing coronary artery calcification in asymptomatic older men and women when taken with recommended amounts of calcium and vitamin D

(Shea et al., 2009)

Vitamin C with/without inorganic nitrate (NO3-)

20 mg/kg Vitamin C and 7 mg/kg potassium NO3-, one dose daily, taken four times with a 7-day washout period between doses

- Vitamin C reduced arterial stiffness in young and elderly people

- Vitamin C reduced systolic, diastolic, and mean blood pressure in older and increased diastolic blood pressure in younger participants

- Combination of Vitamin C and NO3-?additionally reduced diastolic blood pressure and improved arterial stiffness

(Ashor et al., 2020)

α-Lipoic acid (ALA)

600 mg ALA daily in 250 mL 0.9% sodium chloride, intravenous, for 3 weeks

In aged T2DM patients complicated with acute cerebral infarction, ALA reduced the oxidative stress level, lowered hyperglycemia, improved lipid metabolism, and improved brain cell metabolism

(Zhao and Hu, 2014)

Ubiquinol (reduced form of Coenzyme Q10)

200 mg twice a day (QH absorb Jarrow Formulas?).

Oral supplementation started 7 days before and ended 5 days after aortic valve replacement surgery

Ubiquinol supplementation improved myocardial protection and improved systolic function in the follow-up phase in elderly patients after aortic valve replacement surgery

(Orlando et al., 2020)

Zinc + copper

50 mg zinc sulfate and 1 mg cupric sulfate in capsule form daily, for 3 months

Reduced inflammation of the retina and reduced age-related macular degeneration

(Smailhodzic et al., 2014)

Zinc + Chromium

30 mg of zinc as Zn gluconate and/or 400 mg of chromium as Cr picolinate daily, for 6 months

Individual and combined Zn and Cr supplementation reduced lipid peroxidation in plasma, thus exerting antioxidant effects in people with type 2 DM

(Anderson et al., 2001)

Copper

2 mg copper per day as copper glycinate for 8 weeks

Copper supplementation raised the activities of ceruloplasmin in plasma and superoxide dismutase in erythrocytes in middle-aged adults with moderately high cholesterol

(DiSilvestro et al., 2012)

Copper

3 or 6 mg elemental copper per day as copper (II) sulfate for 4 weeks

Increased activity of erythrocyte superoxide dismutase (SOD) and slightly increased activities of ceruloplasmin and white blood cells SOD

(Bügel et al., 2007)

Magnesium

Mg2+?was administered as effervescent tablets (Biolectra? Magnesium 240 forte, containing 243 mg Mg2+) ?in a creeping dose of 1 and 2 tablets each for 3 days followed by 3 tablets for 14 days. Treatment was repeated twice separated by a 2-week washout

Mg2+?partially reversed changes in sleep EEG and the endocrine system that occur during aging

(Held et al., 2002)

Selenium + Coenzyme Q10

200 μg organic selenium plus 200 mg of coenzyme Q10?daily, for 4 years

Supplementation with selenium and Co-Q10 reduced fibrosis in elderly healthy persons, which could improve cardiac function and reduce cardiovascular mortality

(Alehagen et al., 2018)

L-arginine

5 g daily for 4 weeks

L-arginine improved oxidative metabolism and energy expenditure in elite water polo players

(Gambardella et al., 2021)

L-arginine

9 g three times daily for 6 months

L-arginine increased insulin sensitivity in obese patients

(Suliburska et al., 2014)

L-glutamine

0.3 g/kg/day added to 10 g/day of maltodextrin, diluted in 250 mL of water, for 30 days

L-glutamine additionally improved anti-inflammatory response and redox homeostasis in physically active elderly people

(Almeida et al., 2020)

N-acetyl cysteine (NAC)

Capsules with 200 mg NAC were administered at a daily dose of 1.8 g for 6 weeks

NAC treatment improved muscular and cognitive functions of

frail geriatric patients

(Hauer et al., 2003)

β-Alanine

2.4 g/day of β-Alanine, given as three, 800 mg doses with a meal per day, for 28 days

β-Alanine improved endurance exercise capacity and reduced endurance exercise-induced declines in executive function

β-Alanine supplementation can potentially lead to improved muscle strength, decreased fall risk, and improved cardiovascular health.

(Furst et al., 2018)

Ornithine Oxoglutarate (OGO)

10 g daily after lunch, for 2 months

In elderly patients recovering from acute illnesses, OGO improved appetite, body weight, and independence, increased quality-of-life index, and reduced medical cost

(Brocker et al., 1994)

Curcumin

500 mg daily for 12 weeks

Curcumin decreased body weight and reduced arterial stiffness in people with metabolic syndrome

(Alidadi et al., 2021)

Curcumin

2000 mg/day Longvida? pill for 12 weeks

Curcumin improved resistance and conduit artery endothelial function by reducing oxidative stress and increasing nitric oxide production (NO is a vasodilator)

(Santos-Parker et al., 2017)

Melatonin

1.5 mg melatonin (Melaxen?) daily at 22:30 h for two weeks

Melatonin reduced systolic and diastolic blood pressure. The hypotensive effect of melatonin was most pronounced between 3:00 and 8:00 in the morning, i.e. at the time of the highest risk of adverse cardiovascular events. Melatonin also reduced a sudden rise in heart rate in the morning

(Gubin et al., 2016)

Resveratrol

Daily intake of four capsules, two before or at the first main meal and two before or at the second main meal, for 26 weeks. The total dosage was 200 mg of resveratrol and 320 mg of quercetin, added to increase the bioavailability of resveratrol.

- Resveratrol improved memory performance and functional connectivity of the hippocampus in healthy overweight older adults

- Resveratrol reduced peripheral HbA1c, a long-term marker of glucose control.

(Witte et al., 2014)

Resveratrol

500 mg daily for 12 weeks as the addition to meloxicam treatment (15 mg daily) for knee osteoarthritis

Resveratrol reduced the pain severity and decreased serum levels of many inflammatory mediators in patients with knee osteoarthritis

(Marouf et al., 2018)

Resveratrol (Longevinex)

One capsule of Longevinex

containing 100 mg trans resveratrol daily after dinner, for 6 months

Longevinex improved endothelial function in adults with metabolic syndrome already been receiving standard treatment for lifestyle-related disease.

(Fujitaka et al., 2011)

Green tea

Green tea (4 cups/day) or green tea extract (2 capsules of extract purchased from Solaray?, 4 cups water/day) for 8 weeks

Green tea elevated whole blood glutathione concentrations and plasma antioxidant capacity in obese participants with the metabolic syndrome

(Basu et al., 2013)

Green tea extract

?One capsule of extract (containing 379 mg green tea extract and a total of 208 mg of EGCG) per day with the morning meal for 3 months

- Reduced BMI

- Decreased total cholesterol, LDL, and triglycerides

- Increased HDL

- Reduced glucose concentration

- Reduced oxidative stress

(Suliburska et al., 2012)

Matcha Green Tea Powder (contains a variety of active ingredients beneficial to health, such as tea catechins, lutein, and vitamin K)

Matcha green tea powder drink serving as 15 g of powder containing 1.5 g Matcha new green tea powder (Yabukita) with non-dairy creamer and low calories sweetener, twice a day for 12 weeks

Matcha green tea powder had a protective effect against cognitive decline in clinically normal elderly women

(Sakurai et al., 2020)

Phloem powder (manufactured from the bark layer of pine tree)

70 g/day of dried bread (with 14% of phloem powder, containing 62 mg of catechins), consumed throughout the day, for 30 days

Consumption of phloem-fortified bread increased the oxidation resistance of total serum lipids

(Mursu et al., 2005)

LEOPIN ROYAL? (LER)

(non-prescription health-promoting medication in Japan containing aged garlic extract, ginseng, oriental bezoar, velvet antler, Cuscuta seed, and epimedium herb)

1 mL (one capsule full), with normal or warm water, twice daily, for 6 months.

2 mL of LER contains 1.8 mL of concentrated AGE, 273 mg of ginseng extract, 0.15 mL of oriental bezoar tincture, 0.03 mL of velvet antler fluid extract, 30 mg of Cuscuta seed extract, and 5 mg of epimedium herb extract

LER improved somatic and psychological symptoms of aging in males

(Nishimatsu et al., 2014)

Polyphenol-rich extract from grape and blueberry (PEGB)

2 capsules PEBG (each with 300 mg of unique formulation standardized in low-molecular-weight polyphenols) per day (one capsule at least 1 hour after breakfast and one capsule at least 1 hour after dinner) for 24 weeks

PEGB demonstrated a positive effect on verbal episodic memory on healthy elderly with a lower level of memory performance

(Bensalem et al., 2019)

Chlorella pyrenoidosa?drink

27 ml of Chlorella water extract for 90 days (phase I) and vice-versa manner for 90 days (phase II) with 4 weeks of washout period

Chlorella water extract improved antioxidant status and lowered oxidative stress/aging markers in healthy subjects aged between 40 and 75

(Chiu et al., 2021)

Schisandra chinensis Baillon extracts (SCe)

1 g SCe daily for 12 weeks

SCe enhanced skeletal muscle strength in older adults who perform the low-intensity exercise

(Cho and Lee, 2021)

Antioxidant mix containing bacopa, lycopene, astaxanthin, and vitamin B12

once a day for 8 weeks

Improved cognitive function in healthy older adults (aged 60 years or more)

(Crosta et al., 2020)

Fermented Laminaria japonica?(FST)

1.5 g/day of FST for 6 weeks

FST reduced oxidative stress and exerted protective effects against the degenerative effects of aging on short-term memory and physical function in moderately active senior subjects

(Reid et al., 2018)

Cranberry extract beverage

50 mL low calorie, high polyphenol cranberry extract beverage (CEB) daily for 8 weeks

CEB reduced CVD risk factors by improving redox status, vasodilation, glucose homeostasis, and HDL cholesterol in healthy overweight/obese adults.

(Chew et al., 2019)

Cocoa flavanol (CF)

dairy-based cocoa drink containing CFs either at high flavanol (HF; 993 mg flavanols/serving), intermediate flavanol (IF; 520 mg flavanols/serving), or low flavanol (LF; 48 mg flavanols/serving) amounts daily for 8 weeks.

Drinks were provided in individual sachets containing a dry beverage mix; the mix was reconstituted with water according to provided instructions just before consumption

CF consumption improved cognitive performance, improved blood pressure and several metabolic markers, and reduced insulin resistance in a group of cognitively intact older adults

(Mastroiacovo et al., 2015)

Tomato juice (rich in lycopene)

commercially available tomato juice once a day as refreshment 4 times a week for two months

tomato juice reduced serum concentrations of cardiovascular risk factors, ameliorated endothelial dysfunction in patients with metabolic syndrome, and improved glycemic control

by decreasing insulin resistance.

(Tsitsimpikou et al., 2014)

Blueberries

12 g powder of lyophilized, cultivated blueberries in 1 cup of water with each morning and evening meal (equivalent to one cup of fresh blueberries per day) for 90 days

Polyphenols present in blueberries improved cognitive function in healthy older adults

(Rutledge and Sandhu, 2021)

Blueberries

12 g of a lyophilized, standardized blend of Tifblue blueberry, sourced from a single batch of fruit, twice daily, for 90 days (24 g/day, equivalent to 1 cup of fresh blueberries)

Reduced repetition errors during word list recall and increased accuracy during task switching among healthy older adults

(Miller et al., 2018)

Mediterranean diet enriched with virgin olive oil or mixed nuts

Daily dietary changes of common portion sizes during 1 year: +10 g per day of virgin olive oil, +30 g per day of nuts, +100 g per day of vegetables or fruits, +25 g per day of legumes or fresh fatty fish, ?25 g per day of processed meat

MedDiet improved several atherothrombosis biomarkers in older individuals at high cardiovascular risk

(Hernáez et al., 2020)

Mediterranean diet

One year of the daily abundant use of virgin olive oil for cooking and dressing (≥4 tablespoons/day; 10–15 g/tablespoon); daily consumption of at least 2 servings of vegetables (200 g/serving; at least one serving raw or as a salad) and 3 or more units of fresh fruit (125–150 g/unit); weekly consumption of at least 3 servings of legumes (150 g cooked weight/serving), 3 or more servings of fish or seafood (especially oily fish; 100–150 g/serving), and fresh nuts and seeds (3 or more handfuls per week); cooking dishes seasoned with “sofrito” (a slow-cooked homemade sauce with tomato, garlic, onion, aromatic herbs, and olive oil) at least twice a week; a reduction in meat consumption, choosing (skinless) white meat instead of red meat or processed meat (< 1 serving/day); and avoidance of additional fats (butter, margarine, seed oils, creams, etc.) and foods rich in sugar and unhealthy fats (commercial bakery products, chips, precooked food, sugared beverages, etc.)

- Mediterranean diet ?improved the function of endothelial

- Mediterranean diet decreased intracellular ROS production, cellular apoptosis, and endothelial cell senescence while increasing cellular proliferation and angiogenesis

- Mediterranean diet improved endothelial function on the epigenetic level as well, by regulating the levels of certain microRNA

(Yubero-Serrano et al., 2020)

Mediterranean diet

Abundant use of virgin olive oil for cooking and dressing of salads and other dishes (participants were given free extra virgin olive oil and they were told to use the oil as much as they needed in their regular diet), consumption of two or more servings (125 g/serving) per day of vegetables (at least one of them as a salad), three or more servings (125 g/serving) per day of fresh fruit, three or more servings (40 g/serving) per week of legumes; three or more servings (150 g/serving) per week of fish or seafood, three or more servings (25 g/serving) per week of nuts or seeds, white meats instead of red meats or processed meats and regular preparation of a homemade sauce with tomato, garlic, onion, and spices with olive oil to dress vegetables, pasta, rice, and other dishes. The MedDiet was consumed for 1.5 years

MedDiet rich in virgin olive oil improved endothelial function in patients with prediabetes and diabetes

(Torres-Pe?a et al., 2018)

Mediterranean diet

Mediterranean diet (38% of energy from fat: 24% monounsaturated fatty acids (MUFA; provided by virgin olive oil), 10% saturated fatty acids (SFA), 4% polyunsaturated fatty acids (PUFA)) for 4 weeks

Reduced oxidative stress and inflammation

(Lopez-Moreno et al., 2016)

Extra virgin olive oil (EVOO)

25 ml of raw EVOO per day, for 12 weeks

EVOO decreased cholesterol efflux capacity of the HDL of elderly healthy subjects, thus reducing the risk for cardiovascular disease

(Otrante et al., 2021)

Catfish oil enriched with omega-3

1 g of oil daily for 90 days

CO with omega-3 reduced oxidative stress and improved cognitive function in elderly people

(Atmadja et al., 2020)

Argan oil

25 ml/day of virgin argan oil (VAO) taken in a single dose with bread at breakfast for 3 weeks

VAO increased vitamin E concentration, protected plasma, and LDL from oxidation, and improved the antiatherogenic property of HDL

(Cherki et al., 2005)

Pecan-rich diet

pecan-rich diet (15% of total calories) for two 4 weeks periods (I and II) with a two-week washout period between Periods I and II

Pecan-rich diet improved insulin resistance, fasting insulin, and beta-cell function and lowered the risk of cardiometabolic disease in a population of middle-aged and older?overweight or obese adults who are predisposed to developing CVD and/or T2DM

(McKay et al., 2018)

Rapamycin

8 mg/kg rapamycin daily for 90 days.

increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice.?

?

Alessandro Bitto, et al (2016)

Rapamycin

1 mg daily for 4 months

Rapamycin was well tolerated with no unanticipated side effects in older persons

(Kraig et al., 2018)

Rapamycin

3 mg daily oral rapamycin (Rapamune, Wyeth Pharmaceuticals, 1 mg tablets) for 28 days before bladder cancer surgery

Rapamycin improved immune function by modulating activity of T lymphocytes

(Svatek et al., 2019)

RAD001 (inhibitor of mTOR)

0.5 mg RAD001 daily, 5 mg RAD001 weekly, or

20 mg RAD001 weekly for 6 weeks

RAD001 slowed the age-related deterioration of immune function

(Mannick et al., 2014)

RAD001 and/or BEZ235 (inhibitors of mTOR)

0.5 mg of RAD001 once daily, 0.1 mg of RAD001 once daily, 10 mg of BEZ235 once daily, or a combination of 0.1 mg of RAD001 and 10 mg of BEZ235 once daily, for 6 weeks

A combination of RAD001 + BEZ235 decreased rate of infections reported by elderly subjects and increased humoral response to influenza vaccination

(Mannick et al., 2018)

Metformin

500 mg metformin hydrochloride (Merck-Serono) corresponding to 390 mg metformin three times a day, for 2 years

Metformin modulated effectors of pathways that regulate longevity in peripheral blood mononuclear cells of prediabetes people. These data support the potential clinical use of metformin to counteract accelerated aging associated to metabolic diseases

(de Kreutzenberg et al., 2015)

Metformin

Not specified (regular individually prescribed therapy for at least 6 months)

Metformin may reduce the high risk of cardiovascular events in patients with prediabetes with stable angina and nonobstructive coronary stenosis by reducing coronary endothelial dysfunction

(Sardu et al., 2019)

Berberine

Or

Metformin

berberine or metformin (0.5 g t.i.d.) in a 3-month trial.?

?

HbA1c?decreased from 8.1% ± 0.2% to 7.3% ± 0.3% (P<0.001). Fasting plasma insulin and HOMA-IR were reduced by 28.1% and 44.7% (P<0.001), respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were decreased significantly as well.

?

Jun Yin, et al. (2008)

Spermidine

Grain roll with wheat germ for breakfast 6 times a week for 3 months, with 3.3 mg of spermidine in each roll

Or

Rolls baked with wheat bran for breakfast 6 times a week for 3 months, with 1.9 mg of spermidine in each roll

Improved cognitive performance, with a higher dose of spermidine being also effective in people with mild and moderate dementia.

?

Spermidine supplementation has great therapeutic potential in older adults at risk of dementia

(Pekar et al., 2021)

Spermidine

daily dose of 750 mg of spermidine-rich plant extract (with a daily spermidine dose of 1.2 mg) and 510 mg cellulose, dispersed into three capsules, for 3 months

Spermidine improved memory performance in older adults at risk for Alzheimer’s disease

(Wirth et al., 2018)

Nicotinamide riboside chloride (NIAGEN?); NR is a precursor of NAD+, critical signaling molecule and essential substrate for sirtuins, a class of enzymes that mediate several of the beneficial effects of CR in model organisms, including the maintenance of cardiovascular function

500 mg NIAGEN?, twice per day, for 6 weeks

- NR supplementation is well-tolerated in healthy middle-aged and older adults.

- NR stimulated NAD+?metabolism in humans.

- NR reduced systolic blood pressure and aortic stiffness

(Martens et al., 2018)

Nicotinamide Mononucleotide (NMN)

125 mg NMN twice per day, for 8 weeks

NMN increased muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese

(Yoshino et al., 2021)

Caloric restriction (CR)

25% caloric restriction for 2 years (in reality energy intake declined by 480 kcal/d (19.5% CR) during the first 6 months) and then stabilized at 234 kcal/d (9.5% CR) until the end of the study)

CR affected:

- Mental Health: improved mood and quality of life

- Cognition: improved working memory

- Cardiometabolic Risk Markers: decreased fasting insulin, triglycerides, total and LDL cholesterol, increased glucose tolerance, and HDL cholesterol

- Metabolism: decreased sleep core temperature and mass-specific energy expenditure

- Body composition: decreased body weight, fat mass, trunk fat, and increased lean-to-fat ratio

- Reduced inflammation, oxidative stress, and improved immune function

(Dorling et al., 2021)

15% CR over two years

CR slowed down metabolism, decreased body weight, and reduced oxidative stress in healthy, non-obese people

(Redman et al., 2018)

12% CR for 2 years

CR slowed biological aging

(Belsky et al., 2017)

300 to 500 kcal/day restriction combined with two days of Sunnah fasting per week ?for 3 months

CR with Sunnah fasting reduced negative moods including tension, anger, confusion, and total mood disturbance and improved positive mood among aging men (50 to 70 years)

(Hussin et al., 2013)

300 to 500 kcal/day restriction combined with two days of Sunnah fasting per week ?for 3 months

CR with Sunnah fasting was effective in reducing energy intake, body weight and showed improvements in body composition without compromising the quality of life among elderly men

(Teng et al., 2011)

30% CR or 10% CR for 6 months

CR decreased oxidative stress and improved antioxidant defense system in healthy overweight men and women aged 24-42 years

(Meydani et al., 2011)

Dasatinib (D) and Quercetin (Q)

D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks

DQ treatment improved physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time in people with idiopathic pulmonary fibrosis

(Justice et al., 2019)

Dasatinib (D) and Quercetin (Q)

A single 3-day oral treatment regimen with D 100 mg daily and Q1000 mg total daily (500 mg twice daily)

DQ treatment decrease senescent cells in humans

(Hickson et al., 2019)

Rosuvastatin

40 mg per day for 12 weeks

- Rosuvastatin reduced total cholesterol, LDL cholesterol, and triglycerides

- Rosuvastatin reduced atherosclerotic plaques by epigenetic mechanism (reduced level of inhibitory microRNA miR-33b-5p), thus showing anti-atherosclerotic properties

(Santovito et al., 2020)

Atorvastatin

10 mg per day for 8 weeks

Atorvastatin exerted potent anti-atherosclerotic effects by epigenetic mechanism (reduced level of inhibitory microRNA miR-34a) in people with coronary artery disease

(Tabuchi et al., 2012)

Atorvastatin and Rosuvastatin

80 mg atorvastatin or 40 mg rosuvastatin per day for 6 weeks

- Atorvastatin and rosuvastatin reduced levels of total and LDL cholesterol. Atorvastatin additionally increased the level of HDL cholesterol in hyperlipidemic patients

- Atorvastatin and rosuvastatin increased insulin level

- Atorvastatin and rosuvastatin decreased CRP (C-reactive protein) level, thus reducing inflammation

(Thongtang et al., 2011)

Berberine

purified berberine tablets (500 mg orally twice a day), for 12 weeks

Berberine affects CVD (cardiovascular disease) risk factors in men by lowering total cholesterol, as well as possibly lowering LDL-c and increasing testosterone

(Zhao et al., 2021)

Candesartan

8 mg candesartan cilexetil once daily, for 44 months.

If blood pressure did not reach the target BP of <160/90 mm Hg on two consecutive visits separated by a minimum of 2 weeks, the candesartan dose was doubled.

Treatment with candesartan in older adults with hypertension may be effective in reducing cognitive decline associated with hypertension in the areas of attention, episodic memory, and possibly the speed of cognition

(Saxby et al., 2008)

Candesartan or Lisinopril

daily dosage of candesartan 8 mg or capsule of lisinopril 10 mg for 1 year.

If BD did not reach the target value of <140/90 on two consecutive visits separated by 2 weeks, the dosage was increased (16 mg and 32 mg for candesartan or 20 mg and 40 mg for Lisinopril)

Both treatments improved executive function and cognitive performance in older adults with hypertension and mild cognitive impairment.

?

Candesartan was more effective than lisinopril

(Hajjar et al., 2020)

Tadalafil

5 mg once daily for 12 weeks

Tadalafil improved erectile dysfunction (ED) and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS) in sexually active men at least 45 years of age who had a 3-month history of ED and BPH-LUTS for >6 months

(Egerdie et al., 2012)

fullerene

c-60 Olive Oil Solution

50mg fullerene dissolved in 10ml olive oil

33% life span extension

Tarek Baati a, et al

?

?

References

Alehagen, U., Aaseth, J., Alexander, J., Svensson, E., Johansson, P., Larsson, A., 2018. Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality? BioFactors (Oxford, England) 44(2), 137-147. https://doi.org/10.1002/biof.1404?

Alidadi, M., Sahebkar, A., Eslami, S., Vakilian, F., Jarahi, L., Alinezhad-Namaghi, M., Arabi, S.M., Vakili, S., Tohidinezhad, F., Nikooiyan, Y., Norouzy, A., 2021. The Effect of Curcumin Supplementation on Pulse Wave Velocity in Patients with Metabolic Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial, in: Barreto, G.E., Sahebkar, A. (Eds.), Pharmacological Properties of Plant-Derived Natural Products and Implications for Human Health. Springer International Publishing, Cham, pp. 1-11. https://doi.org/10.1007/978-3-030-64872-5_1?

Almeida, E.B., Santos, J.M.B., Paix?o, V., Amaral, J.B., Foster, R., Sperandio, A., Roseira, T., Rossi, M., Cordeiro, T.G., Monteiro, F.R., Amirato, G.R., Santos, C.A.F., Vieira, R.P., Vaisberg, M., Barros, M.P., Bachi, A.L.L., 2020. L-Glutamine Supplementation Improves the Benefits of Combined-Exercise Training on Oral Redox Balance and Inflammatory Status in Elderly Individuals. Oxid Med Cell Longev 2020, 2852181-2852181. https://doi.org/10.1155/2020/2852181?

Anderson, R.A., Roussel, A.M., Zouari, N., Mahjoub, S., Matheau, J.M., Kerkeni, A., 2001. Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. Journal of the American College of Nutrition 20(3), 212-218. https://doi.org/10.1080/07315724.2001.10719034?

Ashor, A.W., Shannon, O.M., Werner, A.-D., Scialo, F., Gilliard, C.N., Cassel, K.S., Seal, C.J., Zheng, D., Mathers, J.C., Siervo, M., 2020. Effects of inorganic nitrate and vitamin C co-supplementation on blood pressure and vascular function in younger and older healthy adults: A randomised double-blind crossover trial. Clinical Nutrition 39(3), 708-717. https://doi.org/10.1016/j.clnu.2019.03.006?

Atmadja, T., Kusharto, C., Sinaga, T., 2020. Supplementation of Catfish (Clarias gariepinus) Oil Enriched with Omega-3 Soft Capsule Improves Oxidative Stress and Cognitive Function in Elderly. Journal of nutritional science and vitaminology 66(Supplement), S47-s50. https://doi.org/10.3177/jnsv.66.S47?

Basu, A., Betts, N.M., Mulugeta, A., Tong, C., Newman, E., Lyons, T.J., 2013. Green tea supplementation increases glutathione and plasma antioxidant capacity in adults with the metabolic syndrome. Nutr Res 33(3), 180-187. https://doi.org/10.1016/j.nutres.2012.12.010?

Belsky, D.W., Huffman, K.M., Pieper, C.F., Shalev, I., Kraus, W.E., 2017. Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis. The journals of gerontology. Series A, Biological sciences and medical sciences 73(1), 4-10. https://doi.org/10.1093/gerona/glx096?

Bensalem, J., Dudonné, S., Etchamendy, N., Pellay, H., Amadieu, C., Gaudout, D., Dubreuil, S., Paradis, M.E., Pomerleau, S., Capuron, L., Hudon, C., Layé, S., Desjardins, Y., Pallet, V., 2019. Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study. The journals of gerontology. Series A, Biological sciences and medical sciences 74(7), 996-1007. https://doi.org/10.1093/gerona/gly166?

Brocker, P., Vellas, B., Albarede, J.L., Poynard, T., 1994. A two-centre, randomized, double-blind trial of ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects. Age and ageing 23(4), 303-306. https://doi.org/10.1093/ageing/23.4.303?

Bügel, S., Harper, A., Rock, E., O'Connor, J.M., Bonham, M.P., Strain, J.J., 2007. Effect of copper supplementation on indices of copper status and certain CVD risk markers in young healthy women. British Journal of Nutrition 94(2), 231-236. https://doi.org/10.1079/BJN20051470?

Chen, H., Liu, S., Ji, L., Wu, T., Ji, Y., Zhou, Y., Zheng, M., 2016. Folic Acid Supplementation Mitigates Alzheimer's Disease by Reducing Inflammation: A Randomized Controlled Trial.?2016, 5912146. https://doi.org/10.1155/2016/5912146?

Cherki, M., Derouiche, A., Drissi, A., El Messal, M., Bamou, Y., Idrissi-Ouadghiri, A., Khalil, A., Adlouni, A., 2005. Consumption of argan oil may have an antiatherogenic effect by improving paraoxonase activities and antioxidant status: Intervention study in healthy men. Nutrition, metabolism, and cardiovascular diseases : NMCD 15(5), 352-360. https://doi.org/10.1016/j.numecd.2004.08.005?

Chew, B., Mathison, B., Kimble, L., McKay, D., Kaspar, K., Khoo, C., Chen, C.Y.O., Blumberg, J., 2019. Chronic consumption of a low calorie, high polyphenol cranberry beverage attenuates inflammation and improves glucoregulation and HDL cholesterol in healthy overweight humans: a randomized controlled trial. Eur J Nutr 58(3), 1223-1235. https://doi.org/10.1007/s00394-018-1643-z?

Chiu, H.F., Lee, H.J., Han, Y.C., Venkatakrishnan, K., Golovinskaia, O., Wang, C.K., 2021. Beneficial effect of Chlorella pyrenoidosa drink on healthy subjects: A randomized, placebo-controlled, double-blind, cross-over clinical trial.?45(4), e13665. https://doi.org/10.1111/jfbc.13665?

Cho, Y.H., Lee, S.Y., 2021. Effect of Schisandra chinensis Baillon extracts and regular low-intensity exercise on muscle strength and mass in older adults: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 113(6), 1440-1446. https://doi.org/10.1093/ajcn/nqaa447?

Crosta, F., Stefani, A., Melani, F., Fabrizzi, P., Nizzardo, A., Grassi, D., Bocale, R., Necozione, S., Lombardi, F., Castelli, V., Cicero, A.F.G., Cimini, A., Ferri, C., Desideri, G., 2020. Improvement of Executive Function after Short-Term Administration of an Antioxidants Mix Containing Bacopa, Lycopene, Astaxanthin and Vitamin B12: The BLAtwelve Study. Nutrients 13(1), 56. https://doi.org/10.3390/nu13010056?

de Kreutzenberg, S.V., Ceolotto, G., Cattelan, A., Pagnin, E., Mazzucato, M., Garagnani, P., Borelli, V., Bacalini, M.G., Franceschi, C., Fadini, G.P., Avogaro, A., 2015. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. Nutrition, metabolism, and cardiovascular diseases : NMCD 25(7), 686-693. https://doi.org/10.1016/j.numecd.2015.03.007?

DiSilvestro, R.A., Joseph, E.L., Zhang, W., Raimo, A.E., Kim, Y.M., 2012. A randomized trial of copper supplementation effects on blood copper enzyme activities and parameters related to cardiovascular health. Metabolism: clinical and experimental 61(9), 1242-1246. https://doi.org/10.1016/j.metabol.2012.02.002?

Dorling, J.L., van Vliet, S., Huffman, K.M., Kraus, W.E., Bhapkar, M., Pieper, C.F., Stewart, T., Das, S.K., Racette, S.B., Roberts, S.B., Ravussin, E., Redman, L.M., Martin, C.K., Group, C.S., 2021. Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2. Nutr Rev 79(1), 98-113. https://doi.org/10.1093/nutrit/nuaa085?

Egerdie, R.B., Auerbach, S., Roehrborn, C.G., Costa, P., Garza, M.S., Esler, A.L., Wong, D.G., Secrest, R.J., 2012. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. The journal of sexual medicine 9(1), 271-281. https://doi.org/10.1111/j.1743-6109.2011.02504.x?

Fujitaka, K., Otani, H., Jo, F., Jo, H., Nomura, E., Iwasaki, M., Nishikawa, M., Iwasaka, T., Das, D.K., 2011. Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Nutrition Research 31(11), 842-847. https://doi.org/10.1016/j.nutres.2011.09.028?

Furst, T., Massaro, A., Miller, C., Williams, B.T., LaMacchia, Z.M., Horvath, P.J., 2018. β-Alanine supplementation increased physical performance and improved executive function following endurance exercise in middle aged individuals. Journal of the International Society of Sports Nutrition 15(1), 32. https://doi.org/10.1186/s12970-018-0238-7?

Gambardella, J., Fiordelisi, A., Spigno, L., Boldrini, L., Lungonelli, G., Di Vaia, E., Santulli, G., Sorriento, D., Cerasuolo, F.A., Trimarco, V., Iaccarino, G., 2021. Effects of Chronic Supplementation of L-Arginine on Physical Fitness in Water Polo Players. Oxid Med Cell Longev 2021, 6684568-6684568. https://doi.org/10.1155/2021/6684568?

Gubin, D.G., Gubin, G.D., Gapon, L.I., Weinert, D., 2016. Daily Melatonin Administration Attenuates Age-Dependent Disturbances of Cardiovascular Rhythms. Current aging science 9(1), 5-13. https://doi.org/10.2174/1874609809666151130220011?

Hajjar, I., Okafor, M., McDaniel, D., Obideen, M., Dee, E., Shokouhi, M., Quyyumi, A.A., Levey, A., Goldstein, F., 2020. Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment: A Randomized Clinical Trial. JAMA Netw Open 3(8), e2012252-e2012252. https://doi.org/10.1001/jamanetworkopen.2020.12252?

Hauer, K., Hildebrandt, W., Sehl, Y., Edler, L., Oster, P., Dr?ge, W., 2003. Improvement in muscular performance and decrease in tumor necrosis factor level in old age after antioxidant treatment. Journal of molecular medicine (Berlin, Germany) 81(2), 118-125. https://doi.org/10.1007/s00109-002-0406-7?

Held, K., Antonijevic, I.A., Künzel, H., Uhr, M., Wetter, T.C., Golly, I.C., Steiger, A., Murck, H., 2002. Oral Mg(2+) supplementation reverses age-related neuroendocrine and sleep EEG changes in humans. Pharmacopsychiatry 35(4), 135-143. https://doi.org/10.1055/s-2002-33195?

Hernáez, á., Casta?er, O., Tresserra-Rimbau, A., Pintó, X., Fitó, M., Casas, R., Martínez-González, M., Corella, D., Salas-Salvadó, J., Lapetra, J., Gómez-Gracia, E., Arós, F., Fiol, M., Serra-Majem, L., Ros, E., Estruch, R., 2020. Mediterranean Diet and Atherothrombosis Biomarkers: A Randomized Controlled Trial. Molecular nutrition & food research 64(20), e2000350. https://doi.org/10.1002/mnfr.202000350?

Hickson, L.J., Langhi Prata, L.G.P., Bobart, S.A., Evans, T.K., Giorgadze, N., Hashmi, S.K., Herrmann, S.M., Jensen, M.D., Jia, Q., Jordan, K.L., Kellogg, T.A., Khosla, S., Koerber, D.M., Lagnado, A.B., Lawson, D.K., LeBrasseur, N.K., Lerman, L.O., McDonald, K.M., McKenzie, T.J., Passos, J.F., Pignolo, R.J., Pirtskhalava, T., Saadiq, I.M., Schaefer, K.K., Textor, S.C., Victorelli, S.G., Volkman, T.L., Xue, A., Wentworth, M.A., Wissler Gerdes, E.O., Zhu, Y., Tchkonia, T., Kirkland, J.L., 2019. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446-456. https://doi.org/10.1016/j.ebiom.2019.08.069?

Hussin, N.M., Shahar, S., Teng, N.I., Ngah, W.Z., Das, S.K., 2013. Efficacy of fasting and calorie restriction (FCR) on mood and depression among ageing men. The journal of nutrition, health & aging 17(8), 674-680. https://doi.org/10.1007/s12603-013-0344-9?

Justice, J.N., Nambiar, A.M., Tchkonia, T., LeBrasseur, N.K., Pascual, R., Hashmi, S.K., Prata, L., Masternak, M.M., Kritchevsky, S.B., Musi, N., Kirkland, J.L., 2019. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554-563. https://doi.org/10.1016/j.ebiom.2018.12.052?

Kraig, E., Linehan, L.A., Liang, H., Romo, T.Q., Liu, Q., Wu, Y., Benavides, A.D., Curiel, T.J., Javors, M.A., Musi, N., Chiodo, L., Koek, W., Gelfond, J.A.L., Kellogg, D.L., Jr., 2018. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol 105, 53-69. https://doi.org/10.1016/j.exger.2017.12.026?

Lopez-Moreno, J., Quintana-Navarro, G.M., Delgado-Lista, J., Garcia-Rios, A., Delgado-Casado, N., Camargo, A., Perez-Martinez, P., Striker, G.E., Tinahones, F.J., Perez-Jimenez, F., Lopez-Miranda, J., Yubero-Serrano, E.M., 2016. Mediterranean Diet Reduces Serum Advanced Glycation End Products and Increases Antioxidant Defenses in Elderly Adults: A Randomized Controlled Trial. Journal of the American Geriatrics Society 64(4), 901-904. https://doi.org/10.1111/jgs.14062?

Ma, F., Wu, T., Zhao, J., Han, F., Marseglia, A., Liu, H., Huang, G., 2016. Effects of 6-Month Folic Acid Supplementation on Cognitive Function and Blood Biomarkers in Mild Cognitive Impairment: A Randomized Controlled Trial in China. The journals of gerontology. Series A, Biological sciences and medical sciences 71(10), 1376-1383. https://doi.org/10.1093/gerona/glv183?

Ma, F., Zhou, X., Li, Q., Zhao, J., Song, A., An, P., Du, Y., Xu, W., Huang, G., 2019. Effects of Folic Acid and Vitamin B12, Alone and in Combination on Cognitive Function and Inflammatory Factors in the Elderly with Mild Cognitive Impairment: A Single-blind Experimental Design. Current Alzheimer research 16(7), 622-632. https://doi.org/10.2174/1567205016666190725144629?

Mannick, J.B., Del Giudice, G., Lattanzi, M., Valiante, N.M., Praestgaard, J., Huang, B., Lonetto, M.A., Maecker, H.T., Kovarik, J., Carson, S., Glass, D.J., Klickstein, L.B., 2014. mTOR inhibition improves immune function in the elderly. Science translational medicine 6(268), 268ra179. https://doi.org/10.1126/scitranslmed.3009892?

Mannick, J.B., Morris, M., Hockey, H.P., 2018. TORC1 inhibition enhances immune function and reduces infections in the elderly.?10(449). https://doi.org/10.1126/scitranslmed.aaq1564?

Marouf, B.H., Hussain, S.A., Ali, Z.S., Ahmmad, R.S., 2018. Resveratrol Supplementation Reduces Pain and Inflammation in Knee Osteoarthritis Patients Treated with Meloxicam: A Randomized Placebo-Controlled Study. Journal of medicinal food. https://doi.org/10.1089/jmf.2017.4176?

Martens, C.R., Denman, B.A., Mazzo, M.R., Armstrong, M.L., Reisdorph, N., McQueen, M.B., Chonchol, M., Seals, D.R., 2018. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun 9(1), 1286-1286. https://doi.org/10.1038/s41467-018-03421-7?

Mastroiacovo, D., Kwik-Uribe, C., Grassi, D., Necozione, S., Raffaele, A., Pistacchio, L., Righetti, R., Bocale, R., Lechiara, M.C., Marini, C., Ferri, C., Desideri, G., 2015. Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial. Am J Clin Nutr 101(3), 538-548. https://doi.org/10.3945/ajcn.114.092189?

McKay, D.L., Eliasziw, M., Chen, C.Y.O., Blumberg, J.B., 2018. A Pecan-Rich Diet Improves Cardiometabolic Risk Factors in Overweight and Obese Adults: A Randomized Controlled Trial. Nutrients 10(3), 339. https://doi.org/10.3390/nu10030339?

Meydani, M., Das, S., Band, M., Epstein, S., Roberts, S., 2011. The effect of caloric restriction and glycemic load on measures of oxidative stress and antioxidants in humans: results from the CALERIE Trial of Human Caloric Restriction. The journal of nutrition, health & aging 15(6), 456-460. https://doi.org/10.1007/s12603-011-0002-z?

Miller, M.G., Hamilton, D.A., Joseph, J.A., Shukitt-Hale, B., 2018. Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial. Eur J Nutr 57(3), 1169-1180. https://doi.org/10.1007/s00394-017-1400-8?

Mursu, J., Voutilainen, S., Nurmi, T., Helleranta, M., Rissanen, T.H., Nurmi, A., Kaikkonen, J., Porkkala-Sarataho, E., Nyyss?nen, K., Virtanen, J.K., Salonen, R., Salonen, J.T., 2005. Polyphenol-rich phloem enhances the resistance of total serum lipids to oxidation in men. Journal of agricultural and food chemistry 53(8), 3017-3022. https://doi.org/10.1021/jf048448x?

Nishimatsu, H., Kitamura, T., Yamada, D., Nomiya, A., Niimi, A., Suzuki, M., Fujimura, T., Fukuhara, H., Nakagawa, T., Enomoto, Y., Kume, H., Igawa, Y., Homma, Y., 2014. Improvement of symptoms of aging in males by a preparation LEOPIN ROYAL containing aged garlic extract and other five of natural medicines - comparison with traditional herbal medicines (Kampo). The aging male : the official journal of the International Society for the Study of the Aging Male 17(2), 112-116. https://doi.org/10.3109/13685538.2013.771328?

Obeid, R., Hübner, U., Bodis, M., Graeber, S., Geisel, J., 2018. Effect of adding B-vitamins to vitamin D and calcium supplementation on CpG methylation of epigenetic aging markers. Nutrition, metabolism, and cardiovascular diseases : NMCD 28(4), 411-417. https://doi.org/10.1016/j.numecd.2017.12.006?

Orlando, P., Sabbatinelli, J., Silvestri, S., Marcheggiani, F., Cirilli, I., Dludla, P.V., Molardi, A., Nicolini, F., Tiano, L., 2020. Ubiquinol supplementation in elderly patients undergoing aortic valve replacement: biochemical and clinical aspects. Aging 12(15), 15514-15531. https://doi.org/10.18632/aging.103742?

Otrante, A., Trigui, A., Walha, R., Berrougui, H., Fulop, T., Khalil, A., 2021. Extra Virgin Olive Oil Prevents the Age-Related Shifts of the Distribution of HDL Subclasses and Improves Their Functionality. Nutrients 13(7), 2235. https://doi.org/10.3390/nu13072235?

Pekar, T., Bruckner, K., Pauschenwein-Frantsich, S., Gschaider, A., Oppliger, M., Willesberger, J., Ungersb?ck, P., Wendzel, A., Kremer, A., Flak, W., Wantke, F., Jarisch, R., 2021. The positive effect of spermidine in older adults suffering from dementia : First results of a 3-month trial. Wien Klin Wochenschr 133(9-10), 484-491. https://doi.org/10.1007/s00508-020-01758-y?

Pekas, E.J., Shin, J., Headid, R.J., Son, W.M., Layec, G., Yadav, S.K., Scott, S.D., Park, S.Y., 2021. Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: a double-blind placebo-controlled randomised crossover clinical trial. The British journal of nutrition 125(2), 161-171. https://doi.org/10.1017/s0007114520002548?

Pusceddu, I., Herrmann, M., Kirsch, S.H., Werner, C., Hübner, U., Bodis, M., Laufs, U., Widmann, T., Wagenpfeil, S., Geisel, J., Herrmann, W., 2017. One-carbon metabolites and telomere length in a prospective and randomized study of B- and/or D-vitamin supplementation. Eur J Nutr 56(5), 1887-1898. https://doi.org/10.1007/s00394-016-1231-z?

Redman, L.M., Smith, S.R., Burton, J.H., Martin, C.K., Il'yasova, D., Ravussin, E., 2018. Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging. Cell Metab 27(4), 805-815.e804. https://doi.org/10.1016/j.cmet.2018.02.019?

Reid, S.N.S., Ryu, J.-K., Kim, Y., Jeon, B.H., 2018. The Effects of Fermented Laminaria japonica on Short-Term Working Memory and Physical Fitness in the Elderly. Evid Based Complement Alternat Med 2018, 8109621-8109621. https://doi.org/10.1155/2018/8109621?

Rossman, M.J., Santos-Parker, J.R., Steward, C.A.C., Bispham, N.Z., Cuevas, L.M., Rosenberg, H.L., Woodward, K.A., Chonchol, M., Gioscia-Ryan, R.A., Murphy, M.P., Seals, D.R., 2018. Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. Hypertension 71(6), 1056-1063. https://doi.org/10.1161/HYPERTENSIONAHA.117.10787?

Rutledge, G.A., Sandhu, A.K., 2021. Blueberry phenolics are associated with cognitive enhancement in supplemented healthy older adults.?12(1), 107-118. https://doi.org/10.1039/d0fo02125c?

Sae-Lee, C., Corsi, S., Barrow, T.M., Kuhnle, G.G.C., Bollati, V., Mathers, J.C., Byun, H.M., 2018. Dietary Intervention Modifies DNA Methylation Age Assessed by the Epigenetic Clock. Molecular nutrition & food research 62(23), e1800092. https://doi.org/10.1002/mnfr.201800092?

Sakurai, K., Shen, C., Ezaki, Y., Inamura, N., Fukushima, Y., Masuoka, N., Hisatsune, T., 2020. Effects of Matcha Green Tea Powder on Cognitive Functions of Community-Dwelling Elderly Individuals. Nutrients 12(12), 3639. https://doi.org/10.3390/nu12123639?

Santos-Parker, J.R., Strahler, T.R., Bassett, C.J., Bispham, N.Z., Chonchol, M.B., Seals, D.R., 2017. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging 9(1), 187-208. https://doi.org/10.18632/aging.101149?

Santovito, D., Marcantonio, P., Mastroiacovo, D., Natarelli, L., Mandolini, C., De Nardis, V., Paganelli, C., De Cesare, D., Affaitati, G., Giamberardino, M.A., Stellin, L., Pinelli, M., Weber, C., De Blasis, G., Occhiuzzi, U., Bucci, M., Desideri, G., Cipollone, F., 2020. High dose rosuvastatin increases ABCA1 transporter in human atherosclerotic plaques in a cholesterol-independent fashion. International journal of cardiology 299, 249-253. https://doi.org/10.1016/j.ijcard.2019.07.094?

Sardu, C., Paolisso, P., Sacra, C., Mauro, C., Minicucci, F., Portoghese, M., Rizzo, M.R., Barbieri, M., Sasso, F.C., D'Onofrio, N., Balestrieri, M.L., Calabrò, P., Paolisso, G., Marfella, R., 2019. Effects of Metformin Therapy on Coronary Endothelial Dysfunction in Patients With Prediabetes With Stable Angina and Nonobstructive Coronary Artery Stenosis: The CODYCE Multicenter Prospective Study. Diabetes care 42(10), 1946-1955. https://doi.org/10.2337/dc18-2356?

Saxby, B.K., Harrington, F., Wesnes, K.A., McKeith, I.G., Ford, G.A., 2008. Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology 70(19 Pt 2), 1858-1866. https://doi.org/10.1212/01.wnl.0000311447.85948.78?

Shea, M.K., O'Donnell, C.J., Hoffmann, U., Dallal, G.E., Dawson-Hughes, B., Ordovas, J.M., Price, P.A., Williamson, M.K., Booth, S.L., 2009. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 89(6), 1799-1807. https://doi.org/10.3945/ajcn.2008.27338?

Smailhodzic, D., van Asten, F., Blom, A.M., Mohlin, F.C., den Hollander, A.I., van de Ven, J.P.H., van Huet, R.A.C., Groenewoud, J.M.M., Tian, Y., Berendschot, T.T.J.M., Lechanteur, Y.T.E., Fauser, S., de Bruijn, C., Daha, M.R., van der Wilt, G.JTHE BATTLE AGAINST AGING

, Hoyng, C.B., Klevering, B.J., 2014. Zinc supplementation inhibits complement activation in age-related macular degeneration. PLoS One 9(11), e112682-e112682. https://doi.org/10.1371/journal.pone.0112682?

Stanhewicz, A.E., Alexander, L.M., Kenney, W.L., 2015. Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms. Clin Sci (Lond) 129(2), 159-167. https://doi.org/10.1042/CS20140821?

Suliburska, J., Bogdanski, P., Szulinska, M., Pupek-Musialik, D., Jablecka, A., 2014. Changes in mineral status are associated with improvements in insulin sensitivity in obese patients following L-arginine supplementation. Eur J Nutr 53(2), 387-393. https://doi.org/10.1007/s00394-013-0533-7?

Suliburska, J., Bogdanski, P., Szulinska, M., Stepien, M., Pupek-Musialik, D., Jablecka, A., 2012. Effects of green tea supplementation on elements, total antioxidants, lipids, and glucose values in the serum of obese patients. Biol Trace Elem Res 149(3), 315-322. https://doi.org/10.1007/s12011-012-9448-z?

Svatek, R.S., Ji, N., de Leon, E., Mukherjee, N.Z., Kabra, A., Hurez, V., Nicolas, M., Michalek, J.E., Javors, M., Wheeler, K., Sharp, Z.D., Livi, C.B., Shu, Z.-J., Henkes, D., Curiel, T.J., 2019. Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer. Cancer Immunol Res 7(3), 466-475. https://doi.org/10.1158/2326-6066.CIR-18-0336?

Tabuchi, T., Satoh, M., Itoh, T., Nakamura, M., 2012. MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. Clin Sci (Lond) 123(3), 161-171. https://doi.org/10.1042/cs20110563?

Teng, N.I., Shahar, S., Manaf, Z.A., Das, S.K., Taha, C.S., Ngah, W.Z., 2011. Efficacy of fasting calorie restriction on quality of life among aging men. Physiology & behavior 104(5), 1059-1064. https://doi.org/10.1016/j.physbeh.2011.07.007?

Thongtang, N., Ai, M., Otokozawa, S., Himbergen, T.V., Asztalos, B.F., Nakajima, K., Stein, E., Jones, P.H., Schaefer, E.J., 2011. Effects of maximal atorvastatin and rosuvastatin treatment on markers of glucose homeostasis and inflammation. Am J Cardiol 107(3), 387-392. https://doi.org/10.1016/j.amjcard.2010.09.031?

Torres-Pe?a, J.D., Garcia-Rios, A., Delgado-Casado, N., Gomez-Luna, P., Alcala-Diaz, J.F., Yubero-Serrano, E.M., Gomez-Delgado, F., Leon-Acu?a, A., Lopez-Moreno, J., Camargo, A., Tinahones, F.J., Delgado-Lista, J., Ordovas, J.M., Perez-Martinez, P., Lopez-Miranda, J., 2018. Mediterranean diet improves endothelial function in patients with diabetes and prediabetes: A report from the CORDIOPREV study. Atherosclerosis 269, 50-56. https://doi.org/10.1016/j.atherosclerosis.2017.12.012?

Tsitsimpikou, C., Tsarouhas, K., Kioukia-Fougia, N., Skondra, C., Fragkiadaki, P., Papalexis, P., Stamatopoulos, P., Kaplanis, I., Hayes, A.W., Tsatsakis, A., Rentoukas, E., 2014. Dietary supplementation with tomato-juice in patients with metabolic syndrome: a suggestion to alleviate detrimental clinical factors. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 74, 9-13. https://doi.org/10.1016/j.fct.2014.08.014?

Wirth, M., Benson, G., Schwarz, C., K?be, T., Grittner, U., Schmitz, D., Sigrist, S.J., Bohlken, J., Stekovic, S., Madeo, F., Fl?el, A., 2018. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex; a journal devoted to the study of the nervous system and behavior 109, 181-188. https://doi.org/10.1016/j.cortex.2018.09.014?

Witte, A.V., Kerti, L., Margulies, D.S., Fl?el, A., 2014. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci 34(23), 7862-7870. https://doi.org/10.1523/JNEUROSCI.0385-14.2014?

Yoshino, M., Yoshino, J., Kayser, B.D., Patti, G.J., Franczyk, M.P., Mills, K.F., Sindelar, M., Pietka, T., Patterson, B.W., Imai, S.-I., Klein, S., 2021. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372(6547), 1224-1229. https://doi.org/10.1126/science.abe9985?

Yubero-Serrano, E.M., Fernandez-Gandara, C., Garcia-Rios, A., Rangel-Zu?iga, O.A., Gutierrez-Mariscal, F.M., Torres-Pe?a, J.D., Marin, C., Lopez-Moreno, J., Casta?o, J.P., Delgado-Lista, J., Ordovas, J.M., Perez-Martinez, P., Lopez-Miranda, J., 2020. Mediterranean diet and endothelial function in patients with coronary heart disease: An analysis of the CORDIOPREV randomized controlled trial. PLoS Med 17(9), e1003282-e1003282. https://doi.org/10.1371/journal.pmed.1003282?

Zhao, J.V., Yeung, W.-F., Chan, Y.-H., Vackova, D., Leung, J.Y.Y., Ip, D.K.M., Zhao, J., Ho, W.-K., Tse, H.-F., Schooling, C.M., 2021. Effect of Berberine on Cardiovascular Disease Risk Factors: A Mechanistic Randomized Controlled Trial. Nutrients 13(8), 2550. https://doi.org/10.3390/nu13082550?

Zhao, L., Hu, F.X., 2014. α-Lipoic acid treatment of aged type 2 diabetes mellitus complicated with acute cerebral infarction. European review for medical and pharmacological sciences 18(23), 3715-3719. https://www.europeanreview.org/wp/wp-content/uploads/3715-3719.pdf?

Tarek Baati a,b , Fanchon Bourasset c , Najla Gharbi d , Leila Njim b , Manef Abderrabba e , Abdelhamid Kerkeni b , Henri Szwarc d , Fathi Moussa d,*, The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene. https://cvws.icloud-content.com/B/AYZ2i7XG1eZlAKv9NSV1pnrM1IFgAXPOnBhVujRnERtk6w4HA4gcRMn7/habibi_tmp_assetEU3U6X.pdf?o=AoUqInr5WcsH56i4CyNfDORXpOwVx6OYiMGjmNrl84xU&v=1&x=3&a=CAog218yL2QzX4uEqm8PHiMfzAGY4RWkOu9RIEPfYoQ7FiASaRDL26bayC8Y69Ld2sgvIgEAUgTM1IFgWgQcRMn7aiSvyUonxRf-ir7ProXs7koXNXs2BJLKVanQPQqcGEIy5hGJA9lyJFEcuwUXjSWM2QJS73P1hm19HPQkIXd7GydFnFykd6IQGvUTxg&e=1634425334&fl=&r=cc04f885-d878-4c2e-b405-63f539ac9376-1&k=y9ERHn_2o_RhjX3KBQbLKw&ckc=com.apple.clouddocs&ckz=com.apple.CloudDocs&p=39&s=FqGMCwZr9B4vgCEb5oQlI5jTkp4&cd=i?

?

Alessandro Bitto,1,? Takashi K Ito,1,? Victor V Pineda,1 Nicolas J LeTexier,1 Heather Z Huang,1 Elissa Sutlief,1 Herman Tung,1 Nicholas Vizzini,1 Belle Chen,1 Kaleb Smith,1 Daniel Meza,1 Masanao Yajima,2 Richard P Beyer,3 Kathleen F Kerr,4 Daniel J Davis,5 Catherine H Gillespie,5 Jessica M Snyder,6 Piper M Treuting,6 and Matt Kaeberlein1,*. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996648/?

?

Jun Yin,a,b,*?Huili Xing,a?and?Jianping Yeb, Efficacy of Berberine in Patients with Type 2 Diabetes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410097/?