Anti-Aging and Senolytic Molecules

What is Anti-Aging Medicine?

Anti-Aging also know as life extension science is the study of slowing down or reversing the aging process. Some scientists look for breakthroughs in areas such as: regenerative medicine, stem cell research, molecular repair, pharmaceuticals and organ replacement.

The sale of anti-aging products is a lucrative business world-wide with sales now generating $50 billion a year.

What are Senescent Cells?

Senescent cells are cells that no longer can divide -- a result of the telomeres on chromosomes becoming too short reaching the Hayflick limit (point where cell division stops) (reference). These cells do not die but secrete molecules which act as poisons causing nearby cells to become senescent. An inflammatory response is one of the hallmarks of cellular senescence. Senescent cells are a major cause of aging. For a detailed description of senescence see: What is Senescence. ( from -- Cell Signaling Technologies)

What are Senolytics?

Senolytics (from the words “senescence” and “lytic” – destroying) -- are a class of small molecules under current research to determine if they can selectively induce death of senescent cells.

Senolytic agents are currently be researched with the goal of being able to delay, prevent, alleviate, or reverse age-related diseases.

Clearing Out Old Cells Increases Life Span of Mice by 25 Percent

"...Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell–transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice..." Nature Medine-source

Caloric Restriction (CR) and anti-aging

"...Despite technological advances, the survival records from longevity experiments remain the most indispensable tool in ageing-related research. A variety of interventions, including medications, genetic manipulations and calorie restriction (CR), have been demonstrated to extend the lifespan of several species. ..We found that CR and genetic manipulations are generally more effective than medications at extending the total lifespan in both models, and CR can improve the ageing pattern of C. elegans...These results suggest that CR or CR mimetics may be the most reasonable and potentially beneficial anti-ageing strategy..." See Calorie restriction is the most reasonable anti-ageing intervention: a meta-analysis of survival curves.. and references therein.

Senescence and aging: the critical roles of p53

"...p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53’s impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging..." see full pubilcation

The IKK/NF-κB signaling pathway in aging

"... The IKK/NF-κB signaling pathway has been proposed to be one of the key mediators of aging. It is activated by genotoxic, oxidative, and inflammatory stresses and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell cycle progression, cell senescence, and inflammation. Transcriptional activity of NF-κB is increased in a variety of tissues with aging and is associated with numerous age-related degenerative diseases including Alzheimer’s, diabetes and osteoporosis. In mouse models, inhibition of NF-κB leads to delayed onset of age-related symptoms and pathologies. In addition, NF-κB activation is linked with many of the known lifespan regulators including insulin/IGF-1, FOXO, SIRT, mTOR, and DNA damage. Thus NF-κB represents a possible therapeutic target for extending mammalian healthspan..." See NF-κB in Aging and Disease.

"...And it's not just NF-kB. If you decrease IKK-beta, which activates NF-kB, you get something similar: longer lived mice...". See : Growing old with NF-kB --

Mtor and Rapamycin --Is Rapamycin the new Aspirin?

Rapamycin also known as Sirolimus has become one of the most talked about and researched small molecules in recent years. It is a compound that in nature is produced by the soil bacterium Streptomyces which was first found in 1965 in a soil sample from Easter Island. Rapamycin was first developed ias an antifungal agent, as it proved effective in suppressing yeast growth. However, it was soon discovered that it also acted as an immunosuppressant, and it has since been used to protect organ transplant patients from organ rejection."... More years went by, and, in 1999, rapamycin received US FDA approval as an immunosuppressant for organ transplants. A derivative was approved to treat kidney cancer in 2007. Then, in 2009, researchers at Jackson Laboratories in Maine discovered the drug’s “fountain of youth” attributes—it extended the lives of lab mice by 6 months or more..." see ref 1 in Rapamycin Molecule. Rapamycin holds the distinction of having been one of the first drugs to have its target identified biochemically: the aptly named protein “mammalian target of rapamycin,” or mTOR. (See the Rapamycin Molecule)

mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review

"...A growing list of evidence suggests that mTOR signaling influences longevity and aging. Inhibition of the mTOR complex 1 (mTORC1) with rapamycin is currently the only known pharmacological treatment that increases lifespan in all model organisms studied. This review discusses the potential mechanisms how mTOR signaling controls lifespan and influences aging-related processes such as cellular senescence, metabolism, and stem cell function. Understanding these processes might provide novel therapeutic approaches to influence longevity and aging-related diseases...Rapamycin is currently the only known pharmacological substance to prolong lifespan in all studied model organisms and the only one in mammals. "

Metformin as Anti-Aging Therapy

"...Metformin is the most widely prescribed oral hypoglycemic medication for type 2 diabetes worldwide. Metformin also retards aging in model organisms and reduces the incidence of aging-related diseases such as neurodegenerative disease and cancer in humans. In spite of its widespread use, the mechanisms by which metformin exerts favorable effects on aging remain largely unknown. Further, not all individuals prescribed metformin derive the same benefit and some develop side effects. .." see: Metformin as Anti-Aging Therapy: Is It for Everyone?

Resveratrol as Anti-Aging Therapy

"...Recently, it has been demonstrated that resveratrol extends the lifespan through significantly increasing SIRT1 activity, resulting in the increase of SIRT1 affinity for both NAD+ and the acetylated substrate, which is also responsible for the longevity caused by CR. Although resveratrol and CR have been widely studied for their potential health benefits, little is known about their comparative effects..." See A comparative study of anti-aging properties and mechanism: resveratrol and caloric restriction and references therein.

NAD+ as Anti-Aging Therapy

"...Nicotinamide adenine dinucleotide (NAD+) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD+ precursors to augment NAD+ bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans..." See: Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults .. and references therein.

Therapeutic potential of boosting NAD+ in aging and age-related diseases ..

"...Emerging evidence implicates that elevation of NAD+ levels may slow or even reverse the aspects of aging and also delay the progression of age-related diseases..."

ISRIB -- Integrated Stress Response Inhibitor --Drug Reverses Age-Related Mental Decline Within Days

 

December 1, 2020

Rapid Rejuvenation of Mental Faculties in Aged Mice Implicates Reversible Physiological ‘Blockage’ Behind Age-Related Cognitive Losses

"...Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals..."

see source

Exercise as Anti-Aging Therapy

"...Physical exercise has been well demonstrated as an effective antiaging intervention. Although exercise certainly cannot reverse the aging process, it does attenuate many of its deleterious systemic and cellular effects..." See: Physical Exercise as an Effective Antiaging Intervention and references therein.

Exercise and the endorphin response

"...Most studies have demonstrated that serum concentrations of endogenous opioids, in particular beta-endorphin and beta-lipotrophin, increase in response to both acute exercise and training programs. Elevated serum beta-endorphin concentrations induced by exercise have been linked to several psychological and physiological changes, including mood state changes and 'exercise-induced euphoria', altered pain perception, menstrual disturbances in female athletes, and the stress responses of numerous hormones (growth hormone, ACTH, prolactin, catecholamines and cortisol). Many reports have described a role for the endorphin response as seen during exercise and have used the opioid receptor antagonist, naloxone, to investigate and verify the degree of involvement of the opioids..In addition, significant associations have been observed between acute exercise-induced changes in pBDNF concentration and cognitive performance in studies assessing memory, and non-significant associations have been found in studies assessing non-memory cognitive domains..." See Healthy Molecules from Exercise.

Meditation and Anti-Aging

Several studies have explored the role of Meditation of the aging process.

Impact of Yoga and Meditation on Cellular Aging in Apparently Healthy Individuals: A Prospective, Open-Label Single-Arm Exploratory Study--"...This study was designed to explore the impact of Yoga and Meditation based lifestyle intervention (YMLI) on cellular aging in apparently healthy individuals... The mean levels of 8-OH2dG, ROS, cortisol, and IL-6 were significantly lower and mean levels of TAC, telomerase activity, β-endorphin, BDNF, and sirtuin-1 were significantly increased (all values p < 0.05) post-YMLI. The mean level of telomere length was increased but the finding was not significant (p = 0.069). YMLI significantly reduced the rate of cellular aging in apparently healthy population." see full article.

See also:
The potential effects of meditation on age-related cognitive decline: a systematic review
Promising Links between Meditation and Reduced (Brain) Aging: An Attempt to Bridge Some Gaps between the Alleged Fountain of Youth and the Youth of the Field

SENOLYTIC AND ANTI-AGING MOLECULES

RAPAMYCIN ---The mechanistic target of rapamycin (mTOR) pathway has a central role in cell activation...

METFORMIN -- The diabetes drug metformin used by some for anti-aging may diminish benefits of aerobic exercise...

QUERCETIN-- AND WITH DASATINIB--The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells...

FISETIN--Of the 10 flavonoids tested, fisetin was the most potent senolytic...

EGCG- The most active component of green tea....

NAD BOOSTERS --'...The cells of the old mice were indistinguishable from the young mice, after just one week of treatment...

SULFORAPHANE-- An isothiocyanate present in cruciferous vegetables activates antioxidant and anti-inflammatory responses by ...

UROLITHIN --Metabolite of Pomegranate compound with anti-aging effects passes human trial...

MITO-Q -- A water soluble fomr of CoQ10 that has excellent absorption and high bioavailability...

HONOKIOL - A bioactive natural product derived from Magnolia Bark have demonstrated ...

CURCUMIN AND ANALOGS -Recent research is focused on the design and synthesis of curcumin analogs as antiproliferative and anti-inflammatory agents...

BERBERINE --berberine has recently been reported to expand life span in Drosophila melanogaster, and attenuate premature cellular senescence

N-ACETYL-CYSTINE (NAC)--"...pretreatment with NAC increased glutathione levels in the older cells and largely helped offset that level of cell death..."

PIPERLONGUMINE - A natural product from the Long pepper with high bioavailability...

RESVERATROL AND PTEROTSILBINE -- Pterostilben chemically similar to resveratrol bute differs from resveratrol by exhibiting increased bioavailability (80% compared to 20% in resveratrol)

SPERMIDINE--Spermidine delays aging in humans ...

ALLICIN -- Allicin is a compound produced when garlic is crushed or chopped. ...

VITAMIN D3 -- Production of the active forms of Vitamin D are reduced by 50% as a result of an age-related decline

VITAMIN K-- evidence suggests vitamin K has an anti-inflammatory action

TOCOTRIENOL(AND WITH QUERCETIN) --Tocotrieniols have been found to exert a synergistic antitumor effect on cancer cells when given in combination....

HSP-90 INHIBITORS --As a novel class of senolytics