Senolytics

From Longevity Wiki

Senolytics (from senile - decrepit and lytic - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells[1][2]

Prehistory

The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.[3] These data were used to scientifically explain a paradox known since ancient times as mithridatism and later called hormesis: taking very small doses of a non-cumulative poison sometimes leads to better health.[4] Obviously, toxins such as hydrogen cyanide, by means of mitohormesis (due to mitophagy), remove old cells with defective mitochondria unable to withstand temporary hypoxia.[5]

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds the cyanogenic glycoside amygdalin. Its simpler derivative obtained by amygdalin hydrolysis referred to as laetrile (patented 1961) or vitamin B17, although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.[6][7] Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.[8]

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.[9] “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. [10]

Senescent cells as a factor of aging and age-associated diseases

The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing aging-related diseases, such as CVD (cardiovascular disease), cancer, diabetes, and kidney disease, ultimately leading to death.

Role of cell competition in ageing according to Marques-Reis & Moreno 2021.[11]

One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.[12][13][14]Cellular Senescence is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.[15][16]

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific[17][18].

The central role of senescent cells in the occurrence of diseases of the elderly.[19]

Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.[18][20]

Among its beneficial actions, senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression, mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.[21][22] Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.[23] Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases. Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,[24] contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - SASP (senescence associated secretory phenotype), which can contribute to tissue damage, inflammation, and the progression of age-related diseases.[19] In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration.[19] Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.[19] In addition, senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations.[25] They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as paracrine senescence, where secreted senescence factors and extracellular vesicles (EVs)[26] can induce senescence (secondary due to paracrine senescence niche) of neighboring cells.[27][28]

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.[29] However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system[15][30][31] and by selecting the fittest cells with the help of Cell Competition,[32][11][33][34] maintaining tissue and organ health.

Markers of cellular senescence

The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which senescence-associated pH6 β-galactosidase,[35] p21CIP1/WAF1,[36] p16INK4a, and intracellular lipofuscin accumulation[37] are prominent.[38] One of the signs of a cell switching to the path of irreversible aging is the de-repression of the p16INK4a gene, which maintains the viability of senescent cells by preventing their apoptosis.[39] It has been shown that the removal of senescent p16INK4a-positive cells can slow the progression of age-related disorders even at later stages of life.[40][41] However, whether cells that express p16INK4a are actually 'senescent cells', and if removal of such cells could cause harm in specific contexts has been questioned by more recent work.[18] Moreover, a limitation of this approach and similar methods that use genetic engineering[42] is the need for manipulations of the genome. It can instead be easier to use small molecule senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics are thought to start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells, such as by differentiation of resident stem cells.[43] Notably, this is dependent on the availability of stem cell pools which are known to decline with aging, and this has been identified as a theoretical limitation of senolytics, if the lack of such stem cells means new tissue is not formed. It has also been speculated that if the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor.[44]

Small molecules of senolytics

Classification of senolytics according to Power H. et al., 2023.[45]

[46]

Dasatinib + Quercetin

Dasatinib and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic. D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.[47]

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects in vivo.[48]

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.[49][50]

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.[51][52][53]

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.[54]

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,[55] it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study NCT02874989 of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.[56]

Long-term study of the intermittent dasatinib plus quercetin (5 mg/kg + 50 mg/kg) exposure (two consecutive days monthly for 6 months) on aging outcomes and inflammation in nonhuman primates resulted in significant positive body composition changes with improvement in immune cell profiles and reduced glycosylated hemoglobin A1c.[57]

A computer-assisted expression analysis study suggested that piperlongumine (a known natural senolytic found in long pepper Piper longum[58]) combination with quercetin (“P+Q”) may be a natural-compound alternative to the combination of dasatinib and quercetin (“D+Q”).[59]

Fisetin

Fisetin is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.[60][61] [62]

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.[63][64]

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.[65][66] Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.[67] Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.[68] Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.[69]

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. [70]

Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice, reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.[62]

In Caenorhabditis elegans fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.[71] However, both the mean and maximum lifespans were significantly extended by fisetin in Caenorhabditis elegans.[72] Lifespan extension by fisetin was accompanied by reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.[72] Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.[72]

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,[70] and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.[73]

Flavonoid 4,4′-dimethoxychalcone

The flavonoid 4,4′-dimethoxychalcone (DMC) is particularly abundant in the plant Angelica keiskei koidzumi, which has been used in Asian traditional medicine, and was documented for its ability to promote autophagy-dependent longevity and health.[74] By inhibiting the enzymatic activity of a metalloenzyme ferrochelatase, DMC induces iron accumulation and further ferroptosis.[75] Since ferrochelatase was highly expressed in senescent cells compared to non-senescent cells DMC inhibited ferrochelatase and induced ferritinophagy, which led to an increase of labile iron pool, triggering ferroptosis of senescent cells.[76]

Curcumin

Although many consider curcumin and its derivatives to be senolytic,[77], there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.[78] However, due to principle of synergistic synthetic lethality,[10] its analog EF24 can have a senolytic effect in combination with other senolytics.[79][80]

Zoledronate

Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the in vivo amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.[81][82] Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.[83][84] In vitro, zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) in vivo, in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.[85]

Anthocyanin

Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.[86] The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.[87][88]

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.[89]

Supramolecular senolytics

Supramolecular senolytics is organic molecules that selectively target receptors overexpressed in the membranes of aging cells. By leveraging the higher levels of reactive oxygen species (ROS) found in aging cells, these molecules promote the formation of disulfide bonds and create oligomers that bind together. Self-assembly of these oligomers occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by cellular uptake into integrin αvβ3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvβ3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells.[90]

Cycloastragenol

Cycloastragenol, a secondary metabolite isolated from Astragalus membrananceus has a wide spectrum of pharmacological functions, including telomere elongation, telomerase activation, anti-inflammatory effects, antioxidative properties[91] and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the Bcl-2 antiapoptotic family proteins and PI3K/AKT/mTOR pathway. [92] Cycloastragenol also suppresses SASP expression, meaning it can act as a senomorphic to reduce the impact of senescent cells on the age-related phenotype.[92]

Fibrates

Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.[93]

Salvestrols

Salvestrol (lat. salvus - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens. Under the influence of the cytochrome P450 enzyme CYP1B1, which was reported to be involved in performance of two important factors of aging: mitochondrial function and reactive oxygen species (ROS) production,[94] and which is expressed in large quantities in cancer cells[95][96] and due to cellular senescence,[97] salvestrols can be converted into metabolites that cause the death of target cells.[98][99][100]

Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena, rooibos tea.[101] and especially tangerines.[102]

p53-regulated apoptosis inducers

FOXO4-DRI

The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between FOXO4 and p53, leading to release of p53 available to trigger p53 mediated apoptosis. [103] Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.[103]

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.[104] FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.[105]

UBX0101

UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,[106] and in the phase 1 trial,[107] no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.[108] -

CUDC-907

CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.[109] Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.[109]

UBX1325

UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.[110]

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.[111]

Macrolide antibiotics

Two macrolide antibiotics, azithromycin and roxithromycin, belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, in in vitro tests with aged fibroblasts, removed approximately 97% of aged cells and thus reduced the number of aged cells by a factor of 25.[112][113] They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,[114][115][116] and promoting of tissue repair.[117] However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.[118] In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.[119] In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.[120][121] In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.[120]

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.[122]

Navitoclax (ABT-263)

Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w[123][124]

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.[24] ABT-263 has been shown to attenuate the development of pulmonary fibrosis.[125][123]

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.[126]

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.[127]

PROTAC technology

Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins[128]

Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).[129] PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.[130] PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.[131]

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.[132] Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.[133][134][135][136]

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.[137]

BET degraders as senolytic drugs

Super-enhancers activate gene transcription and induce tumorigenesis using densely bound proteins BRD4 and master transcription factors (according to Qian, H et al., 2023).[138]

Super-enhancers are large clusters of enhancers that are in close genomic proximity, are densely bound by the BET bromodomain protein BRD4 and master transcription factors, and are characterized by massive H3K27ac and H3K4me signals in ChIP sequencing (Chromatin immunoprecipitation followed by sequencing).[139] Super-enhancers and their reader BRD4 are critical tumorigenic drivers.[138]

Expression of bet-1, the C. elegans ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.[140] Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.[141]

Hetero bifunctional molecule, ARV-825, that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.[142]

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.[143] In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment.[144]

BETd-246, a BRD degrader belonging to the second generation, exhibits favorable selectivity and anti-neoplastic properties. BETd-246 exhibits significant therapeutic efficacy against lung cancer and hematological cancer.[145] BRD4 is also a repressor in cardiac reprogramming, acting primarily through cytokine oncostatin-M, and transient, but not permanent, degradation of BRD4 by a BET degrader, senolytic BETd-246 treatment can enhance cardiac-reprogramming-based regeneration in vivo.[146]

PZ15227

PZ15227 was generated by tethering of the senolytic drug navitoclax (ABT-263) to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.[147] PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.[148]

DT2216

DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.[149] Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

Inhibitors of CRYAB

Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.[150] CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.[151] As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.[152][153][154] In particular, its overexpression can promote tumorigenesis and metastasis.[155][156]

It was found that in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB, and this senolytic turned out to be 25-hydroxycholesterol (25HC), which is an endogenous metabolite of cholesterol biosynthesis.[157] 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients. 25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.[158] So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.[159]

Ginkgetin, oleandrin and periplocin

Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.[160] Of the three, oleandrin was found to be the most effective.

Activatable senolytics

Selective senolytic platform SenTech™ of Rubedo Life Sciences

Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.[35] Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug 5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal) it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.[161] Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.[161] Similar results have been obtained with other such drugs.[162][163]

Photoablation of senescent cells

Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug KSL0608-Se was created for photoablation of senescent cells, which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.[164] In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.[164]

Future target senolytics

The atypical chemokine receptor 3 (ACKR3), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.[165] CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.[166] The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..[165]

[167]

Developments

The SENSOlytic platform is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells. Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.[168] So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

Garcia H. et al., describe a clinically viable gene therapy consisting of a suicide gene under a senescent cell promoter delivered in vivo with Proteo-Lipid Vehicles (PLVs). These PLVs employ fusion-associated small transmembrane (FAST) proteins that can efficiently transduce a wide range of cells in vivo. Selective ablation of target cells is then achieved through the expression of a potent pro-apoptotic transgene driven by a specific senescence-associated promoter such as p16Ink4A or p53. Aged mice treated with FAST-PLV senolytic showed significantly reduced senescent cell burden. Mice treated with senolytic PLVs had an increased median post-treatment survival of 160%, lower clinical frailty, and improved physical and heart function. Spontaneous tumor burden in these mice was reduced.[169]

Senolytic CAR T cells

Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.[30][170] Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.[171][172] For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.[173][174] Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or p16INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.[175]

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.[176] To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis[177] The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.[178][179]



Senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR) can safely eliminate uPAR-positive senescent cells that accumulate during aging.[171] Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.[180]

Senolytic vaccination

Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.[181][182] Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.[182] The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.[182] For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.[181] A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.[183]

The proteins and pathways involved in senescent cells apoptotic resistance

Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.[184] However, once cells becoming senescent, they are more resistant to apoptotic stimuli.[185][186] At least 125 different genes are involved in the aging process,[187][17][188] a set of which, called “SenMayo”, makes it possible to identify old cells.[189][190] Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.[191][192]

Apoptosis

Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.[193] Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.[194] The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.[195] Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.[196][197] IAPs are characterized by the presence of baculoviral repeat domain (BIR) repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.[198] In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.[199]

IAPs are regulated by mitochondria-derived pro-apoptotic factors such as Smac (second mitochondria-derived activator of caspases)[200] and heat shock protein HtrA2 (high-temperature requirement A2) peptidase.[201] Each of them can bind IAPs, thus freeing caspases to activate apoptosis.[202] The BIR domain found in all IAPs interacts with the conserved IAP binding motif (IBM) of caspases. Similar IBMs are found on Smac and HtrA2.[203]

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.[204] BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.[205][194]

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