Senolytic supplements - the ultimate weapon to anti-aging & rejuvenate?

It appears that a rise in the number of senescent cells is connected to chronic illnesses associated with age, as well as a weaker immune system that is unable to destroy them adequately. In recent years, the research of cellular senescence has been increasingly popular, because we have been able to reverse certain aging processes by treating it with “senolytic supplements.”

What is a senolytic or anti-senescent treatment?

A “senolytic” treatment, like the fight against oxidation or glycation, the protection of our telomeres or DNA, the regeneration of protein cells through autophagy, and so on, is a relatively new technique to combat the consequences of aging.

We now have a number of pharmacological and natural compounds that can help senescent cells die off. Many scientists who study human aging have become increasingly interested in senolytics in recent years. So far, two intriguing approaches have been identified:

Make senescent cells active again
Restore sufficient elimination of these old cells, for example by improving the immune defences.

Senescent cells

Senescent cells are cells that are required for tissue repair after inflammation.

Secretory peculiarities result from the cell cycle pause that distinguishes them: SASP (Standardized Assessment of Student Performance) (Senescence-Associated Secretory Phenotype Associated Secretome)

This secretome allows them to be identified in the lab by analyzing p21, p53, or p16ink4, as well as specific Interleukins IL6, IL8, or beta-Galactosidase. Other indicators are now being tested (p38MAPK)

It was able to characterize these senescent cells when they were identified:

They are anti-apoptosis.
They get damages in their DNA.
They are unaffected by growth factors.
They are beta-galactosidase positive.
Their chromatin structure has been altered.
They have mitochondrial dysfunction, which affects their metabolism.
They feature unique surface markings.
They often have shortened telomeres

The accumulation of these senescent cells will therefore give perverted tissues and organs and is associated with most chronic degenerative pathologies.

How do senolytics treat the molecular mechanisms that cause aging and lead to chronic illnesses such as diabetes, neurodegenerative disease, and cardiovascular disease? Low-level inflammation, biochemical alterations in proteins, lipids, mitochondria, and DNA, stem cell failure, and cellular senescence are all linked to aging. The fact that an intervention that targets one of these processes weakens the others[1] demonstrates their interconnectedness. The malfunction that develops over time in the cells can be rectified, resulting in a longer, healthier life.

Fewer defenses against reactive oxygen species

All aging pathways involve reactive oxygen species (ROS). There is a clear link between biological age, the level of reactive oxygen species (ROS) generation, and oxidative tissue damage. ROS is produced mostly by mitochondria. These change DNA proteins, leading in cellular senescence, functional changes, and pathologies[2].

The enzyme super oxide dismutase 1 (SOD1) in the cytosol and SOD2 in the mitochondria converts the superoxide anion O2- generated by the mitochondria into hydrogen peroxide at the mitochondrial level. Catalase and glutathione peroxidases convert this to water and oxygen[3]. Unfortunately, whereas ROS generation rises with aging, glutathione peroxidase production falls[4].

Our immune system: the No. 1 anti-senescent

A study on mice conducted by the Weizman Institute of Science demonstrates this. The rate of age-related disorders rises by boosting the buildup of senescent cells and weakening the immune system. The mice are then given a medication called ABT-737 (a senolytic), which improves their physical condition and performance significantly.

The findings show that the immune system is critical in the removal of senescent cells, and that its degeneration might lead to age-related diseases. We also know that as we become older, our defenses deteriorate, especially after the age of 60.

As a result, it appears that improving our immunity is already a good method to begin the process of body rejuvenation.

Immune defenses have been demonstrated to be important for longevity and even reversing aging in studies , where it is an issue of renewing our thymus.

Ayurvedic medicine also describes one of the most important foundations of health: “Ojas,” the essence of life that pervades our bodies and gives them vitality. Ojas, on the other hand, is described as being closely tied to our immune system.

As a result, keeping a strong immune system is one of the best methods to extend life and delay the onset of age-related disorders.

3 best senolytic supplements

The term “senolytic,” which was recently coined by the scientific community, refers to the ability to destroy senescent cells (i.e. old cells), the presence of which has been established in recent years as one of the causes of aging, along with oxidative stress and telomere shortening. Senolytic supplements are a very breakthrough finding because there was previously no way to fight this process.

Life Extension Senolytic Activator

The best senolytic supplements

To help regulate senescent cell burden and promote systemic rejuvenation, Life Extension Senolytic Activator® combines black tea theaflavins, the plant-derived flavonoid apigenin, and ultra-absorbable versions of the bio-flavonoids quercetin and fisetin.

What Is Senolytic Activator and How Does It Work?

Cellular senescence is a normal element of the aging process in which cells lose their ability to operate properly. Senescent cells can build up over time, interfering with the healthy cells’ day-to-day functions. Senolytic drugs target senescent cells only.

Benefits of Senolytic Activator

Aids the body in the management of senescent cells
Promotes cellular function that is youthful and healthy.
Systemic regeneration is aided by this supplement.
Made with theaflavins and apigenin from black tea, as well as highly absorbable quercetin and fisetin.
Convenient once-a-week dosing

Up to 70% off Best Life Extension coupon & promo codes

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Infiniwell Senolytic – Healthy Aging Support

The best senolytic supplements

This healthy aging support formula was created to aid in the function of the body as it ages.

This senolytic supplement contain

Fisetin (Rhus Succedanea – stem) 100mg
Quercitin (sophora japonica – bud)400mg
Resveratrol (polygonum cuspidatum Sieb. – root)50mg
Pterostilbene (pterocarpus marsupium – wood)50mg
Curcumin (tumeric root)50mg.
Other ingredients: Veggie Capsules (Hypromellose, Titanium Dioxide)

It is especially recommended for anyone looking to maintain good physical condition and optimal health as they age, as well as anyone who is already experiencing age-related problems such as muscle and joint weakness, vision and hearing impairments,heart problems, cognitive decline, or anyone who wants to lower their risk of developing them.

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Super Smart Senolytic Complex

The best senolytic supplements

Senolytic Complex is intended to destroy the senescent cells that cause aging.

Has a quick and long-lasting revitalizing impact on the entire body.
Encourages the self-destruction of senescent cells, which are responsible for aging and age-related health problems (muscle weakness, cognitive decline, cardiovascular problems, chronic inflammation, etc.)
Fisetin, one of the most potent natural senolytic chemicals, is abundant.
Contains a phytosome of quercetin, which is 20 times more absorbable than regular quercetin.
It is based on the most recent scientific study.

This formulation comprises the most potent, natural senolytic substances discovered to date: quercetin phytosome, theaflavin, and, most crucially, fisetin, an amazing flavonoid that is garnering scientific attention.

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What are natural senolytics?

While waiting for the discovery of the molecule capable of destroying our senescent cells without any danger or collateral effect, we will focus on natural substances that have proven themselves because there are some.

Fisetin

Researchers from the University of Minnesota and the Mayo Clinic recently discovered that a plant chemical found in many foods (including strawberries and certain algae) may boost longevity by assisting the body in eliminating aged and damaged cells. Fisetin, a senolytic from the flavonol (antioxidant) family found in fruits and vegetables, is the culprit.

Scientists were therefore able to treat aged mice, enhance their condition of health and lengthen their longevity. The most intriguing aspect is that these favorable outcomes were acquired on animals towards the end of their lives. They did not have to be treated for the rest of their lives to reap the benefits of life. In other words: even an advanced state of aging can be improved this way (in mice, anyway).

It remains to be seen whether this result can be applied to humans, at what doses fisetin could reduce our senescent cells, and whether this does not cause adverse effects (even if it is natural)…

Quercetin

It has mostly been used in conjunction with dasatinib, although it has also been proven to have an impact when given alone (5). It is a flavonoid antioxidant derived from plants (particularly apple and onion) that is often used as a dietary supplement.

A daily dosage of 50mg/kg in humans appears to duplicate the same tissue concentrations as those found in the mice research, indicating a senolytic effect.

It has also been linked to a reduction in the risk of (cerebrovascular accidents, heart attacks, etc.) (7)

Its effect might be aided by resveratrol, which has several anti-aging qualities (9) (8).

Other natural senolytic substances

Piperlongumine (a chemical generated from long pepper) has the benefit of being relatively non-toxic and easily digested by the digestive tract, making it one of the few molecules for which we have demonstrated senolytic efficacy. It has the ability to trigger apoptosis, or compel senescent cells to self-destruct

According to certain investigations (11) curcumin and related compounds are also competent (12).

The Japanese herb ashitaba, which has long been used to treat hypertension and intestinal issues, would have the similar effect.

It’s also worth noting that hydroxybutyrate, which our bodies manufacture in particular during fasting or ketosis (a condition achieved by reducing dietary carbs), has a senolytic impact .

Finally, be aware that physical exercise can also have this effect of senolysis. In mice fed a “fast-food” type diet, the accumulation of senescent cells is less important when exercise is practiced (10).

Mice physically rejuvenated with senolytics

A study that regrows hair

Other scientists have been able to stop the aging process in animals by removing their senescent cells. Treated mice could run twice as far as untreated mice, had their hair regrow, were more active, and their renal function improved (see this 2017 study).

Limits of the study

These senescent cells were eradicated using an investigational medication (FOXO4-DRI) capable of “waking them up” and pushing them to commit cell suicide via apoptosis. However, because it is a synthetic substance developed through study, it is still dangerous to use in humans.

Results based on this idea of removing senescent cells with another synthetic chemical had already been reported in 2016, allowing for a 20 percent increase in the longevity of mice. However, when we consider that simple calorie restriction in mice can extend their lives by 30 to 40%, this conclusion remains small.

In this study, however, the physical improvements and coat regeneration (i.e. a true “rejuvenation” effect) are striking, but calorie restriction did not show.

Therefore, some are planning on FOXO4-dri because, having shown no adverse effects when applied in mice, it is perhaps the most effective and least risky senolytic. To be continued then…

Senolytics at least rejuvenate mice

Others have employed a senolytic medication that combines two products: quercetin (a well-known antioxidant) and dasatinib (a senolytic) (an anticancer). As a result, they were able to eliminate senescent cells while also reducing the inflammation they created. Rodents’ lifetime was enhanced by 36%, and illness was reduced.See the article in the journal Nature.

Towards a new anti-aging treatment?

It is exciting to see that removing these cells can reverse aging in several ways. We will have to see what the real effects are in humans, and above all, the absence of undesirable side effects. In fact, the question is: how to eliminate these old cumbersome cells by natural methods and respectful of our health balance?

Let’s not get carried away too quickly like some media who have already seen it as a new remedy to regrow hair. Even if one can think of it, it is yet another story.

Reducing our senescent cells actually seems very promising, and various studies have shown a real rejuvenation of the tissues which then regain better functions.

Interesting too, and even better: the previous study reveals that the body’s immunity capacity to eliminate its senescent cells comes from 30% of its innate genetics and 70% from environmental factors, i.e. the hygiene of life. So that’s what encourages us to pay particular attention to it.

Treatments’ efficacy and potential negative effects in people have yet to be determined. This research has already begun. The results, albeit being in patients with significant illnesses, would be promising.

It appears that up to 15% of our cells can become senescent as we age, and that around a third of them would have to be killed to have meaningful outcomes (6)

Rapamycin, which has been shown in animal experiments to lengthen longevity and lower the frequency of degenerative disorders, may be able to stop senescent cells from secreting hazardous chemicals. This drug has been thoroughly investigated. It is, however, an immunosuppressive medication with substantial adverse effects.

Apart from experimental molecules and heavy medications, it should be noted that treatment with metformin would have senolytic activity. It is an antidiabetic that has been used for decades, with few adverse effects, and which fairly recent studies have shown may improve longevity. Metformin acts by neutralizing the toxic secretions of senescent cells but it does not eliminate them.

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Can senolytics reduce chronic inflammation?

Chronic low-level inflammation stems in particular from the decline in autophagy function. It aggravates the aging process and the pathologies associated with it. The markers IL-6, CRP and TNF-α increase with age in the absence of any acute cause, due to high levels of ROS. Caloric restriction alleviates this phenomenon.

Biochemical pathways of aging

Interleukin-6 (IL-6) and C-reactive protein (CRP) are two biomarkers of inflammation used to assess chronic low-level inflammation (LGI). Their increase is linked to the expression of pro-inflammatory transcription factors such nuclear factor kappa B (NF-kB)[13]. NF-kB inhibitors lower IL-6 and CRP levels, which may help to halt the aging process.

A meta-analysis looked at the effects of angiotensin II inhibitors (ARBs), metformin, omega-3s, probiotics, resveratrol, and vitamin D on chronic inflammation. This 2018 review focused on randomized controlled trials (RCTs) to evaluate the impact of these drugs on chronic inflammation. In comparison with a placebo, angiotensin II inhibitors, omega-3s and probiotics significantly reduce the level of CRP and IL-6 (including metformin for IL-6) and confirm a senolytic effect. In contrast, neither resveratrol nor vitamin D showed any effect on CRP and IL-6.

Sartans are safe antihypertensive drugs with few adverse effects in normotensive patients. They provide a weak to moderate reduction in IL-6 and CRP[15]. This effect is achieved by blocking the angiotensin II receptor, which inhibits NF-kB.

Metformin has been the most commonly prescribed hypoglycemic drug for more than 60 years, and it is completely safe. In addition to its hypoglycemic impact, it promotes longevity by decreasing the transcription of the NF-kB factor, which has anti-inflammatory and anti-apoptotic properties. CRP levels in her blood are reduced little yet significantly.

CRP and IL-6 levels are reduced by omega-3s in a minor but substantial way, proportional to the length of treatment. Probiotics restore the balance of the elderly microbiota, which favors putrefaction flora over fermentation flora. They suppress the NF-kB pathway, which modulates the immunological response. The effect is mild to strong, depending on the length of treatment, which influences the senolytic spectrum.

Senescence, or when the dysfunctional cell refuses to fade away

Due to upregulation of senescent cell anti-apoptotic pathways (SCAPs), senescent cells resist apoptosis[16]. After only three days of therapy, quercetin and dasatinib induce apoptosis in some, but not all, senescent cells[17]. In elderly cells, this therapy improves vascular reactivity, cardiac ejection fraction, lung function, hepatic steatosis, and osteoporosis[18]. It prevents the intervertebral disc from losing glucosaminoglycans. These senolytic chemicals are effective against age-related degenerative diseases. Senescent cells, on the other hand, exhibit several senescence markers and employ various apoptosis resistance pathways.

Plants produce senolytics that prolong proper cell function

Certain dietary compounds, known as senolytics, exhibit anti-aging characteristics (resveratrol, green tea extract, epicatechin, quercetin and curcumin). Through many mechanisms (reduction of oxidative stress, suppression of low-grade inflammation, induction of autophagy, improvement of mitochondrial function), their daily use can improve health and lengthen life expectancy in numerous animal models.

Plant-derived metabolites called senolytic phytochemicals can be found in vegetables, fruits, grains, nuts, and beverages including wine, tea, and coffee. Food contains roughly 1 gram of phytochemicals each day[19]. Phenolic derivatives, terpenes, betalains, organosulfites, indoles derivatives, glucosinolates, protein inhibitors, and other organic acids are the most common phytochemicals[20].

Phytochemicals can directly remove ROS

Many phytochemicals are antioxidants that can eliminate ROS[21], thanks to their phenolic hydroxyl groups [22]. The more these hydroxyl functions, the more powerful their antioxidant and senolytic capacity.

Senolytics against Covid-19?

Several studies in mice have shown that eliminating part of the senescent cells through the administration of “senolytic” molecules like fisetin or datasinib improved the health and longevity of elderly people [23]; ongoing clinical trials are investigating the effect of these molecules on a variety of age-related chronic diseases, with promising preliminary results [24]. The clinical features of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) infection, particularly its considerably enhanced severity in the elderly, naturally piqued interest in the involvement of senescent cells in COVID-19 (coronavirus disease 2019) and the contribution of SASP to its severity. An article in the journal Science [25] recently addressed this topic.

Exacerbation of SASP upon infection of human cells

The expression of roughly 10 genes (coding for transcription factors or various interleukins like MCP1 [monocyte chemoattractant protein 1]/CCL2 [chemokine ligand 2], TNF-a [tumor necrosis factor alpha], etc.) can be used to detect SASP stimulation. Their expression is raised in human cells that have undergone irradiation-induced senescence, as expected, but treatment of these cells with the S1 protein (Spike protein) of the SARS-CoV-2 virus exacerbates this phenotype and enhances the expression of SASP proteins. Because these are mostly cytokines, one can imagine a link to the “cytokine storm” (cytokine storm) that frequently happens in severe COVID-19 cases.The authors then studied the effect of this SASP on other cells by incubating the latter (non-senescent) with the culture medium (conditioned medium) of senescent cells.

They found a rise in the expression of genes associated in virus entry in the majority of patients, particularly ACE2 (angiotensin converting enzyme 2), which produces the virus receptor, and TMPRSS2 (transmembrane serine protease 2), which encodes a protease necessary for Spike cleavage. As a result, it may be concluded that senescent cells increase the pathogenesis of SARS-CoV-2 by allowing its entry into nearby (non-senescent) cells via the production of SASP.

All in all, these experiments carried out in vitro on cells of human lines, show that indeed senescent cells are more sensitive to viral infections than normal cells, and that their secretion of inflammatory molecules, stimulated by the infection, can act in their environment and increase the severity of the infection.

Senolytics reduce inflammation at coronavirus

The authors then sought to reduce the number of senescent cells in aged mice to find out if this improves their resistance to infection. This reduction can be obtained by administering to the animals, by the oral route, various “senolytic” compounds which have already been characterized. The first employee, fisetin, a natural flavonoid, has a very favorable effect on aged mice, without showing any toxicity. Two other senolytics, usually given in combination, datasinib and quercetin, have also been used.

Datasinib is a tyrosine kinase inhibitor, already used in chemotherapy for hematological cancers, and quercetin a plant flavonoid whose structure is close to that of fisetin. Many experimental combinations are possible depending on the duration of exposure of mice to NME and the administration regimen of the senolytic molecule.

From mouse to human

Even if the authors establish that the main species in the pathology reported is the MHV virus, a close relative, the mouse model employed in this study is not perfect: infection by microbial flora from “wild” mice (NME) is much less exact and controllable than infection by the SARS-CoV-2 virus. However, unless transgenic strains expressing multiple human proteins are created, the laboratory mouse is not susceptible to the virus that causes COVID-19 [26].

As a result, the NME system is still a viable option in practice. To summarize the findings, we discovered that senescent cells in elderly mice maintain a certain amount of inflammation connected to SASP protein release, but this level is very low in young mice.Infection with the virus exacerbates inflammation in older mice, to the point of damaging surrounding tissues, while it remains moderate in young mice. Treatment with senolytics (fisetin, datasinib and/or quercetin) eliminates some of the senescent cells and preserves the tissues, thus greatly increasing the survival of the treated animals.

How about in people? The removal of senescent cells is a viable route for treating a viral illness like SARS-CoV-2, in which age is a major risk factor. Because the senolytics discussed in this article have already been used in people (mostly as anticancer treatments), they do not require a phase I clinical trial to test their tolerability and pharmacodynamics; instead, phase II trials can be started right away to examine their efficacy.

At least two trials are now underway, both led by James Kirkland (Mayo Clinic), one of the senior writers of the aforementioned article [25].These are trials in due form (randomised trial versus placebo and double-blind). These trials therefore concern a moderate number (but this is usual for a phase II) and will only give a significant result if the therapeutic effect is significant – but this is a reasonable expectation.

We thus await these results with bated breath, because the preclinical data are highly promising, and the rationale of the treatment is flawless, as it involves treating a viral illness whose severity is significantly related to age through the eradication of senescent cells. The hunt for COVID-19-targeting medicines has so far been fruitless; let us hope that this time our hopes are not dashed!

In conclusion

Eliminating senescent cells is very appealing. It is a path still little explored in anti-aging medicine but which seems very interesting. Until now, it has mainly been a question of fighting against oxidation, chronic inflammation, glycation… to stimulate our mechanisms of cell regeneration and energy production but not to eliminate those cells that make our body grow old. and worn.

Specialists in the field, such as Dr. Judith Campisi, explain, however, that senescent cells also seem to play a beneficial role when they are not too invasive. The right measure would be, as always, to find a balance between “too much” and “not enough”.

While waiting for senolytic treatments, which would be specifically dedicated to “rejuvenation”, boosting your immune defenses appears to be an excellent solution. We already know that regular physical activity and fasting improve our immunity, and therefore promote the elimination of excessive senescent cells. This is already a very good start.

Afterwards, we can actually consider using natural products as an accompaniment, as seen above. This is a possibility that is already relevant because these substances are easy to find.

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