SENOTHERAPEUTICS: NOVEL ANTI-AGING THERAPIES FOR CELLULAR SENESCENCE

At the cutting edge of anti-aging medicine, scientists have begun to uncover the cellular pathways that drive the aging process. As a result, senotherapeutics have recently emerged as candidate agents for targeting prime compounds capable of regulating these pathways.

What Are Senotherapeutics?

Senotherapeutics refer to two types of novel therapies currently being developed in order to lessen the symptoms of aging; namely senolytic and senostatic agents. These agents target senescent cells and reside at the forefront of anti-aging medicine.

What Are Senescent Cells?

Senescent cells are cells that have aged. Younger cells become senescent through a lifetime of inflammation, wear and tear; which translates to aging at the macro level. Through this process, cells lose their ability to regenerate and respond by making necessary adaptations – the net result of which is cellular senescence. The body generates more senescent cells throughout life, which contributes towards the age-related changes in health and metabolism unique to the elderly.

These aged cells have a markedly different metabolism to their younger counterparts. On average, senescent cells produce more inflammation than normal cells and this is known to perpetuate the aging process. They are not able to respond to, or produce, the same hormones or neurotransmitters as younger cells. Furthermore, senescent cells do not grow and appear to be resistant to programmable cell death (apoptosis) as well as cellular repair (autophagy). Tissues with senescent cells in them thus have trouble with cellular turnover and are less capable of regeneration. Moreover, they greatly increase the risk for developing cancer, the incidence of which is noted to be higher in the elderly population.

Senotherapeutics have been shown in animal studies to reduce the number of senescent cells as well as increase longevity and lower the risk for developing age-related diseases.^[1]

Senolytics

Senolytics are chemical compounds that promote the programmed death of senescent cells. These compounds work best in combination with senostatics, which inhibit the activity of senescent cells and serve to slow down the aging process. Senolytics act on senescent cells in a way that promotes apoptosis. When senescent cells are allowed to die off, new cells can grow that are more capable of renewal and which produce less inflammation.

Many of the anti-aging benefits of consuming a healthy diet arise from the natural senolytics found in nutrient-dense foods. These compounds and synthetic alternatives are being explored in the field of anti-aging and regenerative medicine.

Senostatics

Other compounds that block the inflammation associated with senescent cells are also being investigated. These are known as senostatic agents. Senostatic agents inhibit the inflammation secreted by aged cells and can slow down the aging process by preventing senescence in younger cells. Senomorphics are another name used to refer to senostatics.

Often senolytic compounds have senostatic properties that enhance their anti-aging properties, as discussed below.

Why Opt for Senotherapeutics? When Aging Mirrors Pathology

It seems obvious that one would want to opt for senotherapeutics in order to combat some of the negative effects of aging. However, not all aging is prone to negative effects that require treatment.

There appear to be two subtypes of senescent cells that distinguish between two types of aging: helper senescent cells and deleterious senescent cells.^[2]

1. Helper senescent cells do not produce inflammation and are not resistant to apoptosis. These will be removed by the immune system when discovered, which may be slower or compromised in the immune-suppressed or aged immune system. Helper senescent cells are known to be associated with graceful aging and minimal age-related health concerns.
2. Deleterious senescent cells are the true target cells for senotherapeutics, as these are responsible for senescence-induced inflammation and are resistant to immune detection and apoptosis. Accumulations of deleterious senescent cells are linked with the progression of age-related diseases and what is referred to as ‘pathological aging’.^[3]

Senotherapeutics could be employed in the future to mitigate disease-related pathology, rather than reverse the effects of healthy aging. Research indicates that short senotherapeutic interventions are most effective for preventing the onset and progression of senescence, as opposed to long-term treatment.^[4]

Senescent cells may play a role in the development and progression of several diseases, even in younger individuals. Some of these include obesity, diabetes, muscle wasting diseases, cancer, osteoarthritis, ataxia, psoriasis, liver diseases, lung diseases and more.^[5]

Thus, senotherapeutics may also be administered to those with chronic ailments in future. More research is required to verify whether senotherapeutics would benefit non-aged individuals with disease.

Common Targets for Senolytics and Senostatics

Senolytics specifically target apoptosis in select senescent cell types, while senostatics have a much broader range of action that target a much broader range of cells.

Senolytic Anti-Apoptotics

All pathways that induce apoptosis typically increase intracellular inflammation through the release of free radical particles that demolish the cell. When a cell is destroyed or damaged, loose cellular components serve as danger signals to nearby cells. In response, these nearby cells become inflammatory. Too much inflammation in this manner can cause extensive tissue damage and can increase the number of senescent cells in the area.

There are multiple biochemical pathways that senolytics can target in order to promote apoptosis (cell death). Six prime ones are being explored currently that are discussed below as unique classes of senolytic.

Not all senotherapeutics are able to target all types of senescent cells in the body and many of their effects are still being studied. Preadipocytes, endothelial cells, and senescent immune cells are some of the most common senescent cell types, with specific responsiveness towards senolytics. Other types of senescent cells studied include fibroblasts, stem cells, senescent cancer cells, and senescent immune cells^[6].

Senolytics may also affect normal cell types, potentially causing widespread apoptosis to occur and suppressing immune function.

Senostatic SASP Inhibitors

Senostatic agents serve to block SASP (Senescence-Associated Secretory Phenotype) which refers to all forms of senescent inflammation and neuroendocrine activity. In this sense, many senostatics serve as antioxidants, anti-inflammatories, hormone therapeutics, and neurotransmitter regulators.

Many senostatics will also inhibit cellular pathways known to trigger the transformation of a normal cell into a senescent one, thereby reducing their production. mTOR, p53, and NFkB are examples of common inflammatory pathways known to promote cellular senescence.

For this reason, senolytics are highly synergistic with senostatics, which serve to lower inflammation and block the development of aged cells. A few classes of senolytics may double-up as senostatics including p53 binding inhibitors and kinase inhibitors.

The other actions of these agents will determine their suitability for the individual in question, including benefits and side effects.

Novel Senotherapeutic Drugs

Currently, the majority of senotherapeutics are pre-existing drugs that have been screened for senolytic and senostatic properties. Trials are underway to approve the use of these medications for treating senescence in specific cell types; as well as to assess their safety, efficacy, and best mode of delivery.

1. Kinase Inhibitors

Kinases are enzymes that are used to add a phosphate to another molecule in order to activate or deactivate it. Kinase inhibitors can be used to induce apoptosis in senescent cells by blocking or activating certain molecules in prime chemical pathways.

These are seen as one of the most potent classes of senolytics as members of this class are effective against all types of senescent cell lines tested, including immune cells^[7]; whereas other types are more selective.

• UBX0101 is a p53 inhibitor currently being investigated for treating osteoarthritis in the knee^[8]. In animal studies, injecting this compound into the cartilage and synovial fluid of joints eliminated senescent cells that were contributing towards the development of osteoarthritis. UBX0101 specifically blocks p53 from binding to MDM2, which reduces the risk for cancer^[9] and increases the chances of cellular apoptosis.
• Dasatinib is a chemotherapeutic drug that has been shown to induce apoptosis in senescent cells, particularly when combined with quercetin (a natural senolytic). It selectively inhibits tyrosine kinase, but is able to act on multiple senescent cell receptors. Dasatinib and quercetin have been proven to work on preadipocytes, endothelial cells, fibroblasts, and bone marrow stem cells. It is currently in phase I/II trials for treating several age-related disorders.

2. p53 Binding Inhibitors

p53 is a tumor-suppressor protein that plays an important role in regulating cellular growth processes, including cell-cycle arrest, apoptosis, and senescence^[10]. The actions of p53 vary depending on what it binds to, which depends on the activity of the cell. Selective binding inhibitors of p53 prevent it from attaching to molecules that would promote senescence, freeing it up in order to promote apoptosis instead. ^[11]

All senescent cell types appear to respond to p53 binding inhibitors. There is one well-studied inhibitor studied to-date:

• FOXO4-DRI Peptide is a synthetic molecule that resembles FOXO4 peptides. Natural FOXO4 peptides in the cell bind to p53 and promote cellular senescence. FOXO4-DRI mimics FOXO4, binds to p53 and deactivates it, resulting in the demolition of the senescent cell. It is one of the strongest known senolytics and has been proven to be effective for treating senescent fibroblasts and chondrocytes (cartilage-producing cells). Further investigation is required to approve FOXO4-DRI peptide for treating senescent cell buildup in osteoarthritis^[12].

3. HSP-90 inhibitors

Heat Shock Protein 90 (HSP90) is a protein that is involved in protein folding, cellular repair, and chaperoning other proteins to various parts of the cell. When inhibited, proteins that rely on HSP90 are often also inhibited, some of which can trigger cellular senescence. Specific HSP90 inhibitors are being investigated in this context in order to accurately promote apoptosis of senescent cells.^[13]

This class of senolytic can be made more effective when coupled with a p53 inhibitor or a Bcl-2 family inhibitor. Examples of HSP-90 Inhibitors include:

• 17-AAG consists of geldanamycin and tanespimycin. These potent senolytics are able to induce apoptosis in senescent cells without affecting healthy ones^[14]. It has been shown to be senolytic in fibroblasts, stem cells, and endothelial cells, but not preadipocytes.
• 17-DMAG refers to Alvespimycin. This drug was shown to extend the lifespan of aged mice, increased apoptosis in senescent cells, as well as offer senostatic benefits.^[15]

All HSP90 inhibitors appear to lower age-related inflammation, doubling up as senostatics.

4. Bcl-2 Family Inhibitors

The Bcl-2 family of proteins regulates cell death through altering the permeability of the outer membrane of the mitochondria (the power house of the cell). If too permeable, the contents of the mitochondria spill out, triggering a cellular reaction that leads to apoptosis.^[16]

Most known Bcl-2 inhibitors were originally developed for chemotherapy in order to promote apoptosis in cancer cells. Cancer cells sometimes revert to cellular senescence in order to evade the immune system, thus it is theoretically possible that most chemo drugs will serve as senolytics as well.

• Navitoclax (ABT-263) is a potent chemodrug^[17] and senolytic that was found to effectively eradicate senescent stem cells found in the muscles, blood, fat, and bones of rats. Unfortunately, it was also shown to eradicate healthy bone cells and inhibit the ability of bone stem cells to contribute successfully towards bone mineralization, resulting in reduced bone mass and an increased risk of osteoporosis^[18]. For this reason and others, Navitoclax has been put aside in the quest for an ideal senolytic.
• ABT-737 is another chemotherapeutic drug with senolytic properties that serves to promote apoptosis in senescent cells through inhibiting Bcl-2 family proteins. It was also found that ABT-737 can induce apoptosis bythrough inhibiting the activation of p53 in skin cells of the lung^[19] and endothelial liver cells^[20].
• A1331852 and A1155463 are two similar Bcl-2 family inhibitors^[21] that have been proven to be less toxic than Navitoclax and more potent than fisetin (see natural compounds below). They are effective for inducing apoptosis in fibroblasts and endothelial cells but not in preadipocytes.^[22]
• Cardiac Glycosides are medications conventionally prescribed to treat heart conditions that were found to have strong senolytic properties^[23]. Proscillaridin A, Ouabain, or Digoxin have been shown to increase the levels of pro-apoptotic Bcl-2 family molecules, which serve to inhibit the anti-apoptotic ones and promote apoptosis.^[24] This is a different approach to the other Bcl-2 family inhibitors listed above, which work by inhibiting anti-apoptotic Bcl-2 family proteins. Cardiac glycosides can therefore be used in combination with other Bcl-2 inhibitors in order to enhance their efficacy.

Bcl-2 family inhibitors are generally effective against senescent endothelial cells, but have different selectivity for other cell types. Senescent preadipocytes are resistant to Bcl-2 family inhibitors.

5. Histone Deacetylase Inhibitors

Histone deacetylase (HDAC) is an enzyme that prevents DNA transcription, inhibiting the expression of genes and their influence on the cell. Most senescent cells show a reduced level of histone deacetylase and inhibitors typically promote cellular senescence under normal circumstances^[25]. However, this class of drug has been proven useful for those with “senescent cancer.”

In contrast to normal cells, some types of cancer cells use HDAC to revert to senescence to escape immune detection. HDAC inhibitors have been shown to eliminate malignant senescent cells^[26].

• Panobinostat is an FDA-approved HDAC inhibitor, primarily used for treating resistant cancers such as non-small cell lung cancer and neck squamous cell carcinomas^[27]. It was found out that the very thing that made panobinostat effective over other chemo drugs was its ability to induce apoptosis in senescent cancer cells of these types.

Chemotherapy-induced senescent cells also have a tendency for elevated HDAC and can be treated using HDAC inhibitors. HDAC inhibitors may also reverse regular senescence when administered in conjunction with a p53 binding inhibitor^[28], as they increase the potency of these agents.

6. Senostatics

Senostatics have been paid less attention than senolytics and often convey more of a broad-spectrum approach.

This is due to the nature of cellular senescence. Senescent cells are not uniform in the SASP factors they secrete. Furthermore, pathways involved in senescence and SASP production intersect with ordinary metabolic processes in healthy cells. Examples include NFkB, p38, GATA4, mTOR, BRD4, and cGAS/STING which all govern vital cellular processes across all cell types. Hence, senostatics are potentially damaging to healthy cells with minimal anti-aging benefits, warranting caution and lots more research.^[29]

Nonetheless, several senostatics are being explored in order to enhance the efficacy of senolytics by lowering inflammation and inhibiting senescence. Mild senostatic agents appear to be more efficacious and less harmful than potent ones in this regard.

A few experimental senostatic agents currently under investigation include the following:

• Metformin is a prime anti-diabetic drug that serves to regulate blood sugar levels. It inhibits inflammatory markers associated with cellular senescence by blocking NFkB and mTOR^[30]. It can also promote apoptosis in senescent cells by inhibiting senescence-related kinases and p53 binding. Metformin may be a promising senostatic option for senescence in elderly patients with insulin resistance and/or obesity.
• Aspirin is a well-known painkiller and anti-inflammatory that has been recently documented to display senostatic and senolytic properties as well. The prime action of aspirin is to block COX-2 receptors in order to inhibit pain-related inflammation. This serves to reduce age-related inflammation and inhibit p53 accumulation, preventing the transformation of healthy cells into senescent ones as well as getting rid of senescent cells.^[31]

​7. Natural Compounds

Several natural antioxidant compounds found throughout whole foods and herbs have senolytic properties. These compounds have formed their own class of senolytic as they often perform multiple senotherapeutic actions and are used to enhance the efficacy of selective synthetic senolytics.

The properties of natural senolytic compounds also coincide with the health benefits associated with consuming nutrient-dense diets, abundant in antioxidant-rich and mildly senolytic foods.

• Quercetin is well-known for being a potent antioxidant phytochemical and for enhancing the efficacy of other senolytics, such as Dasatinib. This combination has proven to decrease the number of senescent cells in mice with age-related diseases, such as intervertebral disc degeneration^[32]. Low doses of quercetin alone increased the lifespans of mice^[33], serving as an anti-SASP agent and kinase inhibitor of several kinases related to senescence^[34]. Second generation drugs using nanoparticle-modified quercetin have been developed which improve upon the senotherapeutic actions of quercetin.^[35] Quercetin-rich foods include leeks, onions, cranberries, cherries, blueberries, herbs such as oregano, fennel, and dill, spinach, kale, chillies, asparagus, and broccoli.^[36]
• Fisetin proved to be the most potent senolytic compound out of a panel of 10 that included quercetin and epigallocatechin gallate^[37]. Fisetin proved more potent at reducing SASP factors and reversing senescence in fibroblasts, endothelial cells, and preadipocytes. It was able to suppress senescence without a need for repeat applications. The results were selective, without evidence for deleterious effects in other cells, when applied in low concentrations. At high concentrations, fisetin can be cytotoxic to normal cell types.
• Synthetic Fisetin Analogues have been developed that appear to be less toxic to non-senescent cells than a pure fisetin extract^[38]. Further testing is required to prove that these would be more effective for the elderly than taking fisetin as a supplement or consuming fisetin-rich foods. Foods high in trace amounts of fisetin include most fruits and vegetables, including apples, persimmons, grapes, strawberries, cucumbers, and onions.
• Piperlongumine was found to be senolytic towards lung fibroblasts, through a novel mechanism involving the reduction of oxidation resistance 1 (OXR1)^{[39] [40]}. In studies, piperlongumine has been used to enhance the efficacy of curcumin, another potent senolytic, antioxidant compound with traditionally poor bioavailability. The combination increased bioavailability and senotherapeutic benefits of both compounds.^[41]
• Epigallocatechin Gallate (EGCG) is a tannin found in green tea that was proven to lower the number of senescent fibroblasts in skin and chondrocytes in cartilage. In preadipocytes, EGCG was able to suppress senescence, inhibit p53 binding, SASP factors, and inhibit anti-apoptotic factors. EGCG is known to extend lifespan in animal studies, protect skin and lower inflammation in many tissues. ^[42]
• Olive Polyphenols have been shown to collectively act as senolytic and senostatic agents, capable of enhancing the efficacy of other senotherapeutics. They have been shown to lower SASP factors such as mTOR, reverse senescence and inhibit p53 binding in fibroblasts.

Other examples of natural compounds with senotherapeutic properties include resveratrol, luteolin, phloretin, kaempferol, apigenin, naringenin, daidzen, and genistein.^[43]

Complementary Treatments That Enhance Immune Clearance

In some elderly individuals, the immune system becomes senescent, with the risk increasing in advanced aging. As a result, immune cells function at a lesser capacity, being less able to detect threats, proliferate, and mount an optimal defense. This is known as immunosenescence.^{[44] [45]}

Furthermore, senescent cells contain mechanisms for escaping immune detection, which contributes to their accumulation. Immune boosting therapies have been shown to enhance the efficacy of senolytics, by improving the immune clearance of deceased senescent cells.

Current therapeutics increase the sensitivity of natural killer cells and CD4+ T cells to senescent cells. These include:

• CAR T Cell Therapy. CAR stands for Chimeric Antigen Receptor. CAR T Cells are genetically engineered T cells that are primed for specific surface receptors, ensuring that any cells with these receptors are demolished and removed from the body once injected into the patient. This therapy was first designed as a treatment for cancer and has since been applied to targeting senescent cells.
• Senescent Cell Receptor Antibodies. This treatment primes immune cells indirectly against senescent cell receptors by offering antibodies against them. The antibodies bind to specific cell receptors and neutralize them, while simultaneously serving as a beacon for the immune system to remove the cell. They are delivered in liposomal or nanoparticle form.

Conclusion

Aged cells of a certain genotype drive the negative aspects of aging, as well as age-related disease processes. Senotherapeutics are able to target cellular pathways in these cells in order to improve quality of life during aging, slow down rapid aging in healthy cells, decrease the number of aged cells as well as block the inflammation they secrete. These agents may also be able to help treat age-related disorders in the future.

Research highlights how combinations of senolytics and senostatic agents are able to maximize the efficacy of senotherapy. Future research is directed towards exploring the selectivity, effective dosages, and safety of these agents. Enhancing immune function is a requirement for improving the efficacy of senotherapeutics in those with senescent or compromised immune function. Natural antioxidant compounds can further enhance the benefits associated with senotherapeutic drugs and are found in many commonly consumed whole foods.

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