Content

  1. Rapamycin and mTOR inhibitors
  2. Senolytics
  3. Metformin
  4. Acarbose
  5. Spermidine
  6. NAD+ Enhancers
  7. Lithium
  8. Non-steroidal anti-inflammatory drugs (NSAIDs)
  9. Reverse transcriptase inhibitors
  10. Blood rejuvenation
  11. Microbiome
  12. Glucosamine
  13. Glycine
  14. 17α-estradiol

Increasing life expectancy and declining fertility lead to an aging population: in many countries, more people are over 65 than under 5. Moreover, healthy life expectancy is less than life expectancy since aging is the leading risk factor for cancer, neurodegenerative, and cardiovascular diseases.

Animal studies have shown that slowing down aging and extending lifespan is possible. For a person, age-related disease prevention strategies include exercise, diet, and a healthy lifestyle. However, these measures are not enough to prevent aging, the mechanisms of which include damage to genetic material, cellular aging, disruption of cell metabolism and mitochondrial function, disruption of intercellular interaction, and stem cell function.

The most promising anti-aging strategies include mild metabolic reduction with rapamycin, removal of senescent cells, stem cell rejuvenation, and microbiome transfer. The fundamental mechanisms these strategies work are increased autophagy and decreased age-related inflammation.

Geroprotectors are small molecules, drugs, and natural products that fight the mechanisms of aging. In 2020, Nature published a review of the most researched geroprotectors:

  • increase lifespan in animal studies;
  • improve human aging biomarkers;
  • have minimal side effects when used in a therapeutic dose;
  • effective in several species of mammals;
  • have low toxicity;
  • affect the mechanisms of aging, ideally in humans;
  • increase the body’s resistance to stress factors;
  • protect against age-related diseases.

The international review team divided geroprotectors into two groups:

  1. Geroprotectors that met most of the above criteria effectively affected the aging mechanisms.
  2. New promising compounds and long-established geroprotectors that met fewer criteria or showed inconsistent results in studies on the effects of aging.

Geroprotectors of the first group: rapamycin and mTOR inhibitors, senolytics, metformin, acarbose, spermidine, NAD+ enhancers, and lithium (points 1-7).

1. Rapamycin and mTOR inhibitors

Rapamycin is an antifungal agent isolated from bacteria in a soil sample from Easter Island in 1960. Rapamycin has immunosuppressive and antiproliferative properties. Rapamycin analogs, both sirolimus and its derivatives, are used as immunomodulators to prevent transplant rejection, as a chemotherapeutic agent in cancer, and to avoid re-narrowing the lumen of stented vessels after heart surgery.

Rapamycin binds to the FKBP12 protein, forming a molecular complex with mTOR, which destabilizes and suppresses the mTORC1 protein complex, the primary cell and body physiology regulator. mTORC1 regulates growth factors, nutrition, oxidative stress, cell growth, and various cellular processes, including autophagy, ribosome biogenesis, protein synthesis and metabolism, and lipid, nucleotide, and glucose metabolism.

Genetic and pharmacological suppression of mTORC1 activity can increase lifespan in budding yeasts, nematodes, and fruit flies. In addition, rapamycin prolongs the mean and maximum lifespan of mice from 9-20 months. Remarkably, rapamycin increases the remaining lifespan of mice by up to 60%, even when treatment is started at 20 months of age—65 years in human terms. Furthermore, a short six-week treatment started at the same age can delay aging. Genetic suppression of mTOR signaling in mice also extends lifespan and delays aging.

Rapamycin prolongs not only life expectancy but also health. This effect can be explained by:

  • Rapamycin has antitumor activity;
  • Rapamycin slows or prevents multiple age-related changes, including changes in arterial structure and function, cognitive impairment, cardiac hypertrophy and diastolic dysfunction, periodontitis, ovarian dysfunction, immune aging, fatty liver, myocardial cell abnormalities, endometrial cysts, adrenal tumors, decreased spontaneous activity and loss of tendon elasticity;
  • Rapamycin protects against type 2 diabetes, Alzheimer’s, Parkinson’s and Huntington’s diseases, Leigh syndrome, lung disease, and cardiovascular syndromes.

Although rapamycin prolongs lifespan and may prevent age-related decline in learning and memory, it does not affect many other body functions and even impairs some functions. Thus, rapamycin increases the severity of cataracts and testicular degeneration.

The efficacy and safety of rapamycin have been studied in dogs and monkeys. Middle-aged dogs tolerated ten weeks of non-immunosuppressive rapamycin treatment well. Rapamycin produced no significant side effects and improved left ventricular systolic and diastolic function, especially in dogs with low cardiac function. In marmosets with age-related pathologies, 14 months of rapamycin administration did not affect body weight, activity, blood lipid concentrations, and markers of glucose metabolism. Rapamycin activates the system to maintain the protein pool necessary for cell function.

The clinical use of rapamycin is limited by its toxic side effects:

  • hyperglycemia;
  • hyperlipidemia;
  • toxicity to the kidneys;
  • impaired wound healing;
  • decrease in the number of platelets in the blood;
  • immune suppression.

Rapamycin may counter the aging of the immune system. A human study showed that six weeks of treatment with the mTOR inhibitor RAD001, a rapamycin analog, improved response to influenza vaccination in elderly volunteers. Antibody titers to two of the three influenza strains in the vaccine increased 1.2-fold. RAD001 was the most potent contributor to influenza protection in high-risk individuals.

2. Senolytics

Cellular aging is a permanent stop of the cell cycle, as a result of which cells stop dividing. Among the causes of cellular aging are replicative exhaustion and DNA damage. Aging cells become resistant to the action of mechanisms of programmed cell death – apoptosis.

Senescent cells secrete pro-inflammatory molecules and enzymes – SASP, a secretory phenotype associated with aging. During aging, tissues accumulate up to 15% of senescent cells, contributing to tissue damage. SASP attracts inflammatory cells, which cause inappropriate cell death and fibrosis and suppress stem cell function. Cellular aging contributes to age-related diseases such as osteoporosis, atherosclerosis, hepatic steatosis, pulmonary fibrosis, and osteoarthritis.

Cellular aging is involved in tissue formation during development and wound healing. Macrophages remove aging and damaged cells, and the number of cells is maintained by dividing young, healthy cells.

Cellular senescence can both promote cancer development and prevent it. DNA damage in cells increases the risk of developing cancer. Senescent cells resist apoptosis and secrete pro-inflammatory cytokines that can promote cell migration, growth and invasion, new blood vessel formation, and metastasis. On the other hand, if cells with damaged DNA die and are removed by macrophages, the risk of cancer will decrease.

Mouse studies have shown that:

Medicines that can be used to prevent age-related diseases:

  • Senolytics – selectively cause the death of aging cells. Short-term administration is possible, the advantage of which is that cell aging remains unchanged during wound healing. Since senescent cells express different markers and use other apoptosis resistance mechanisms, senolytics can act selectively on specific cell types.
  • Senostatics – destroy SASP. Require continuous intake as senescent cells persist. Since the composition of SASP depends on the type of cells and factors that cause aging, the action of senostatics can be directed to specific types of aging cells.

Data from senolytic dasatinib and quercetin studies in mice:

  • Combining quercetin with dasatinib reduced the number of senescent cells in white adipose tissue and liver, increased cardiac ejection fraction and vascular endothelial function in aged mice, reduced the number of senescent cells in some tissues, and increased lifespan. A side effect of dasatinib is thrombocytopenia.
  • Intermittent administration of quercetin and dasatinib improved vasomotor function in aged mice, leading to improved cardiovascular function and increased exercise tolerance. Also, the mice had reduced osteoporosis and weakness.
  • In old mice, the combination of dasatinib and quercetin increased life remaining by 36% and did not increase morbidity in later life.
  • Combined treatment with dasatinib and quercetin slowed uterine aging.

Fisetin is a flavonoid in strawberries, apples, persimmons, and onions. Fisetin gives fruits their yellow color. Fisetin has senolytic properties. Administration of fisetin to aged mice reduced age-related diseases and increased mean and maximum lifespans.

The cardiac glycosides digoxin, digitoxin, and ouabain are potent and specific senolytics. These drugs lead to cellular acidification. Senescent cells already have an acidic pH, so cardiac glycosides induce their apoptosis. Cardiac glycosides treat congestive heart failure and cardiac arrhythmias; senolytic effects are achieved at clinical doses.

A study in patients with idiopathic pulmonary fibrosis showed that combination treatment with dasatinib and quercetin improved physical functions, as measured by 6-minute walking, 4m walking speed, and the time the patient could stand up and sit in a chair five times. Treatment did not affect SASP. However, improvement in physical function was correlated with changes in SASP-associated matrix remodeling proteins, miRNAs, and pro-inflammatory cytokines. A clinical trial is also underway to treat osteoarthritis with senolytic UBX0101.

The clinical use of senolytics is hampered by the fact that it is not known how senolytics affect non-senescent cells. In addition, it is essential to time the senolytic treatment, as the therapy can deplete the stem cells. Another issue is the clearance of dead aging cells.

3. Metformin

Metformin is a drug that lowers blood glucose levels by inhibiting hepatic gluconeogenesis, stimulating glycolysis, and increasing insulin sensitivity. Metformin is used to treat type 2 diabetes.

Metformin may slow aging. In nematodes, metformin prolongs lifespan by 36%. This effect can be explained by:

  • Metformin activates AMPK, an enzyme that regulates the cell’s uptake and oxidation of glucose and fatty acids. Activated AMPK reduces hepatic glucose production, increases glucose uptake by skeletal muscle, stimulates oxidation, and inhibits fatty acid synthesis. By activating AMPK, metformin prolongs the life of the musculoskeletal system.
  • Activation of AMPK increases mitochondrial production of reactive oxygen species, which triggers stress defense mechanisms and increases life expectancy. The mechanism of lifespan extension based on mitochondrial oxidative stress is called mitohormesis.
  • Metformin inhibits the mTORC1 target of rapamycin, a protein complex that regulates cell growth and nutrition, oxidative stress, autophagy, protein, lipid, and glucose synthesis and metabolism. Suppression of mTORC1 prolongs lifespan. [see “Rapamycin”]
  • Metformin alters the microbiome with anti-inflammatory effects. Metformin suppresses the expression of genes encoding inflammatory cytokines that are observed during cellular aging. This property may underlie the ability of metformin to downregulate SASP in aging cells.

In studies in Drosophila and mice, metformin has shown conflicting results. Metformin did not affect lifespan in Drosophila, although it activated AMPK and reduced lipid stores. In cancer-prone mice, metformin increased lifespan and inhibited carcinogenesis. In long-lived and outbred mice, metformin alone did not significantly prolong lifespan, but metformin in combination with rapamycin did significantly prolong life. Although metformin did not increase lifespan in long-lived mice, it may be effective in stressful situations that shorten lifespan.

Human studies have shown that metformin is associated with reduced morbidity and mortality from cardiovascular disease, reduced incidence of cancer, overall mortality, depression, and frailty-related illnesses. Metformin also protects against neurodegeneration and chronic kidney and liver diseases. However, all of these studies compared type 2 diabetic patients treated with metformin with the general population. Therefore, it is unclear whether metformin will benefit people who do not have diabetes.

A study in healthy 70-year-olds showed that metformin taken for six weeks affected not only metabolic genes and pathways but also collagen and mitochondrial genes in adipose tissue and DNA repair genes in muscle, highlighting its targeting for multiple signs of aging.

Metformin is safe. However, in some elderly patients, adding metformin to exercise attenuated its principal effect, increasing insulin sensitivity. Metformin also prevented the increase in mitochondrial respiration of skeletal muscles, which usually occurs during exercise.

4. Acarbose

Acarbose is a bacterial product that inhibits the activity of enzymes necessary to digest carbohydrates. Acarbose treats type 2 diabetes by preventing hyperglycemia, causing weight loss, and improving glycemic control.

Metabolic disorders often accompany aging, and type 2 diabetes is a risk factor for age-related conditions such as cardiovascular disease, kidney disease, cancer, and dementia. Acarbose may improve glycemic control during aging. In a rat study, acarbose reversed age-related glucose intolerance. Also, acarbose is considered a drug that mimics the effect of starvation.

Mice studies have demonstrated the anti-aging effects of acarbose:

  • Acarbose increased life expectancy in males by 22% but only by 5% in females. Maximum life span was significantly increased in both sexes: in males by 11% and in females by 9%.
  • Acarbose decreased body weight more in females than males, reduced fasting blood glucose and plasma insulin-like growth factor 1 levels in both sexes and reduced fasting insulin levels only in males.
  • Acarbose increased mice’s lifespan, reducing male lung tumors, both sexes’ liver degeneration, and glomerulosclerosis in females. In males, acarbose reduced hypothalamic inflammation and reversed male-specific insulin insensitivity and glucose intolerance, which would explain the more significant effect of acarbose on male longevity.
  • Acarbose alters the gut’s microbiome and composition of short-chain fatty acids, associated with increased lifespan.

Side effects of acarbose: flatulence, soft stools, abdominal discomfort.

5. Spermidine

Spermidine is a natural polyamine essential for gene expression control, apoptosis, autophagy, cell growth, and proliferation. With age, spermidine levels in the body decrease.

Spermidine is a geroprotector. Adding spermidine to the diet prolongs the lifespan of yeast, hookworms, fruit flies, and mice. The addition of spermidine to the nutrient medium increases the survival of human immune cells. In Drosophila, increased spermidine production increases lifespan by reducing insulin and insulin-like growth factor signaling. A human study found that high levels of spermidine in the diet were associated with reduced all-cause mortality.

The geroprotective action of spermidine can be explained by the fact that it:

  • Enhances autophagy. In rats, increased dietary spermidine enhances autophagy, mitophagy, biogenesis, and mitochondrial function in the heart and improves cardiac muscle cell function. If autophagy is blocked, spermidine stops working.
  • Protects cardiac function. In mice, supplementation with spermidine slows the age-related decline in cardiovascular function. In humans, high levels of spermidine in the diet are associated with lower blood pressure and lower incidence of cardiovascular disease.
  • Protects immune function. Autophagy is reduced in B- and T-cells of old mice. A 6-week treatment with spermidine increased autophagy and improved B-cell function. Also, spermidine supplementation prevented human B-cell aging.
  • Reduces oxidative stress.

Spermidine can be used to prevent osteoarthritis. Spermidine prevents the decrease in polyamine synthesis and autophagy in aging cartilage tissues. Spermidine may also improve stem cell function in the muscles of older mice, promoting muscle recovery. In Drosophila and mice, spermidine has a neuroprotective effect: it protects synapses from aging and promotes optic nerve regeneration.

Polyamines, which include spermidine, should be used with caution. The reason is that the biosynthesis of polyamines is suppressed to treat and prevent cancer. Polyamines are essential for cell reproduction, which is not desirable in cancer.

6. NAD+ Enhancers

NAD+ is a coenzyme essential for cell metabolism. NAD+ is involved in cellular redox reactions. NAD+ is required to activate sirtuins, signaling proteins that affect aging, cell death, inflammation, and cell resistance to stress.

NAD+ levels decrease with age, contributing to a decrease in sirtuin activity. NAD+ is not taken up by cells, so it is impossible to add NAD+ directly, but it is possible to increase NAD+ synthesis. The most commonly used drugs to increase NAD+ levels are nicotinamide riboside (NR, a form of vitamin B3) and nicotinamide mononucleotide (NMN, a derivative of vitamin B3).

Effects of increasing NAD+ levels:

NR and NMN are natural compounds currently under investigation in humans. NR and NMN differ in bioavailability and stability. NR is bioavailable, safe, and raises NAD+ levels. Administration of NR to older adults for three weeks reduced levels of inflammatory cytokines. However, in obese men with insulin resistance, NR did not improve metabolism.

7. Lithium

In the middle of the 19th century, lithium carbonate was used to treat cancer. Now, it is used to treat bipolar disorder.

Lithium has anti-aging properties:

The geroprotective effect of lithium has not yet been proven in mammals. High doses of lithium are toxic, so lithium is not widely used in the long term. If lithium’s anti-aging effect depends on autophagy’s activation, then it is possible to combine lithium with other autophagy stimulants, such as mTORC1 inhibitors, so that lower doses of lithium can be used, which will have fewer side effects.

Geroprotectors of the second group: non-steroidal anti-inflammatory drugs, reverse transcriptase inhibitors, blood rejuvenation, microbiome, glucosamine, glycine, 17α-estradiol (points 8-14).

8. Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are used to treat mild to moderate pain and, in higher doses, to reduce inflammation. Examples of NSAIDs are aspirin, ibuprofen, celecoxib, and nitroflurbiprofen. NSAIDs inhibit COX enzymes for synthesizing prostaglandins, increasing pain receptors’ sensitivity. NSAIDs also have antithrombotic and antioxidant activity.

Results of animal studies of the anti-aging properties of NSAIDs:

  • Aspirin increases the lifespan of nematodes, fruit flies, and male mice.
  • In mammals, the effects of aspirin include activation of AMPK and subsequent inhibition of mTORC1, which may influence the aging process.
  • Ibuprofen increases the lifespan of yeast, nematodes, and fruit flies by inhibiting the tryptophan transporter, an essential amino acid required for protein synthesis. Inhibition of the tryptophan transporter reduces intracellular amino acid stores, inhibiting mTOR.
  • Nitroflurbiprofen does not affect the lifespan of mice.

Epidemiological and laboratory studies have linked NSAIDs to protection against age-related diseases:

A side effect of aspirin is an increased risk of severe gastrointestinal bleeding.

Clinical trials of aspirin for the prevention of age-related diseases did not confirm epidemiological and laboratory data:

9. Reverse transcriptase inhibitors

Reverse transcriptase is an enzyme required for reverse transcription, that is, the transfer of genetic information from RNA to DNA. Reverse transcription allows mobile sections of DNA to move within the genome, resulting in the synthesis of complementary DNA (cDNA). Reverse transcription is also needed for telomere lengthening. In addition, viruses use reverse transcription to reproduce.

Mobile DNA regions are a source of genome instability; their activation is associated with age-related diseases. During aging, cDNA accumulates in the cell cytoplasm, which activates the type I interferon response. The IFN-I response may contribute to SASP accumulation and chronic inflammation associated with aging.

Nucleoside reverse transcriptase inhibitors (NRTIs) are used to treat HIV. NRTIs reduce age-related pathologies in mice. The NRTIs lamivudine and stavudine minimize DNA damage, suppress pathology, and prolong lifespan in mice prone to premature aging. In aged mice, lamivudine reduces SASP and inflammation.

NRTIs are toxic to mitochondria. Impaired mitochondrial function leads to increased production of reactive oxygen species, contributing to protein, lipid, and DNA damage. Side effects of NRTIs are peripheral neuropathy, myopathy, lipodystrophy, hepatic steatosis, and lactic acidosis.

10. Blood rejuvenation

During aging, intercellular communication is disrupted, which contributes to age-related inflammation. Also, during aging, the properties of the blood deteriorate, which leads to a decrease in the functions of organs and tissues.

Studies in mice have shown that young blood improves the regenerative capacity of stem cells in the muscles, liver, spinal cord, and brain of old mice. Young blood can also prevent age-related changes in the kidneys, a decrease in β-cell replication, and a decrease in the ability to repair bones and tissue regeneration.

Human umbilical cord plasma injected into immunocompromised mice triggered gene expression in synaptic plasticity in the hippocampus, leading to enhanced learning and long-term memory.

In older people, the level of GDF11 protein, growth differentiation factor 11, decreases. This protein regulates the development of bones and the central nervous system. GDF11 deficiency leads to a decrease in the number of stem cells. Injecting young blood into old mice increased GDF11 levels, which helped reduce age-related cardiac hypertrophy. Also, increasing GDF11 levels restored stem cell function and structure, increased strength and endurance in aging mice, and increased cerebral blood flow, neural stem cell proliferation, olfactory neurogenesis, and olfactory function.

Other studies have shown that serum GDF11 levels in rats and humans increase with age and that GDF11 administration suppresses muscle regeneration and stem cell division in mice.

The TIMP2 protein, an inhibitor of metalloproteinase 2, is another candidate for rejuvenating the aging hippocampus. Injecting aged mice with TIMP2 improved learning and memory, whereas depleting plasma TIMP2 abolished the anti-aging effect.

VCAM1 protein levels increase in the plasma of mice and humans with age and in response to inflammation. The introduction of anti-VCAM1 antibodies or genetic deletion of VCAM1, especially in brain endothelial cells, prevented microglia reactivity and cognitive deficits.

In mice with Alzheimer’s disease, administration of young plasma reduced molecular abnormalities in the hippocampus and improved working and associative memory. A study in patients with mild to moderate dementia associated with Alzheimer’s showed that young plasma administration was safe and well tolerated.

11. Microbiome

With age, the composition of the gut microbiome and the abundance of gut microorganisms change. Calorie restriction improves microbiome composition and health. The transfer of the gut microbiome from calorie-restricted mice to microbiome-free mice reduced weight gain, increased glucose tolerance and insulin sensitivity, and promoted the darkening of white fat and the development of beige adipose tissue, which can generate heat rather than store energy.

In older fish, the transfer of a young gut microbiome delayed age-related changes in microbiome composition, improved swimming skills, and extended lifespan.

These microbiome transfer effects are likely associated with a change in the composition of metabolic products produced under the microbiome’s influence or in response. Identifying these metabolic changes will help understand how the microbiome needs to be manipulated to improve health during aging.

12. Glucosamine

Glucosamine is used as a dietary supplement for people with osteoarthritis. Glucosamine has antioxidant and anti-inflammatory effects, inhibits mTOR, and stimulates autophagy, so it may help prevent and treat other diseases, including neurological deficits, cancer, skin and cardiovascular diseases.

Glucosamine increases nematodes’ lifespan and slightly increases old mice’s lifespan. This effect is not due to glucosamine but to a mechanism miming a low-carb diet. Taking glucosamine activated AMPK and increased the production of reactive oxygen species by mitochondria, and a moderate increase in ROS improved immunity and life expectancy.

13. Glycine

Glycine is an amino acid that is part of the body’s proteins. Glycine sources include red meat, seeds, and turkey. Glycine is also available as a dietary supplement.

Taking glycine increases the average and maximum lifespan of mice, rats, and nematodes. In female rodents, glycine supplementation is associated with weight loss. Glycine also has anticancer and anti-inflammatory effects in rodents.

In people with metabolic diseases, taking glycine may slow the progression to type 2 diabetes.

Glycine supplementation is preferable to red meat consumption. Several studies have shown that decreased amino acid levels are associated with increased lifespan. Thus, Japanese scientists reported that high consumption of animal protein, especially red meat, may be related to the development of age-related diseases, and a diet low in animal protein, especially red meat, may benefit health and longevity. One reason is the high content of the amino acid methionine in red meat, which inhibits autophagy. On the other hand, the glycine contained in red meat is essential for methionine clearance in the liver. Methionine restriction increases lifespan, but this restriction is difficult to implement in practice, so that glycine supplementation may be a preferable alternative to red meat consumption.

14. 17α-estradiol

17α-estradiol (17α-E2) is a non-feminizing estrogen with reduced affinity for the estrogen receptor.

In male mice, 17α-E2 increased lifespan. The effect was associated with increased insulin sensitivity and glucose tolerance. For a therapeutic effect, 17α-estradiol needs sex hormones. 17α-E2 did not affect females and castrated males, but a metabolic response was observed in spayed females.

In young mice, 17α-E2 reduced total body weight and increased the muscle-to-fat ratio. However, 17α-E2 preserved body weight and muscle strength in aged male mice. Females and castrated males did not affect 17α-E2.

In obese male mice, 17α-E2 reduced body weight without reducing muscle mass and reduced visceral adiposity and hepatic lipid deposition. This effect was associated with decreased food intake due to activation of hypothalamic anorexigenic pathways. 17α-E2 increased AMPK activity and suppressed mTORC1 in visceral adipose tissue but not liver and muscle. 17α-E2 also reduced inflammation in adipose tissue and systemic inflammation.

17α-E2 may have beneficial effects on brain function. 17α-E2 is the predominant form of estradiol in rodent brains. 17α-E2 may play a neuroprotective role in humans. Laboratory studies have shown that 17α-E2 protects against oxidative stress and amyloid toxicity associated with Alzheimer’s and Parkinson’s diseases.

Conclusion

Aging is a complex process, and no single geroprotective intervention has improved all aspects of aging, although caloric restriction has been the most effective. Concerning pharmacological interventions, animal studies have shown that combining drugs that target different aging mechanisms may be most effective. The most promising strategies are moderate suppression of mTORC1, senostasis and senolysis, improving the composition of the intestinal microbiome, and reducing inflammation.

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