What are senolytics? Benefits, side-effects and research

The increasing number of people at least 65 years and above has led to a population aging phenomenon. According to the World Health Organisation, It is estimated that by 2030, at least 2.1 billion people or roughly 1 in 6 people, will be over 60 years old [1]. 

Along with the aging of the population is the increased prevalence of long-term diseases such as Alzheimer’s, neurodegenerative disorders, cardiovascular diseases, type 2 diabetes, osteoarthritis and other autoimmune disorders and even cancer [1]. Aging is recognised as one of the factors that contribute to these conditions. As one ages, the ability of a cell to repair itself and of tissues to heal are often compromised. Mechanisms in place to combat hyperlipidemia, hyperglycaemia and other abnormal reactions or responses in the body are not as efficient as when one is younger. Many scientists believe that fighting aging or delaying its progression is one the primary keys in also combatting many of the chronic conditions present today. 

We have come a long way in understanding cellular processes and how aging occurs. One of the promising strategies in reversing or delaying cellular aging involves the use of senolytics. 

What are senolytics? 

Senolytics are groups of compounds that remove senescent cells. Animal model studies [2] have shown that these compounds can slow specific aspects of aging. 

When a cell matures and ages, it is expected to die through apoptosis or programmed cell death [3]. Apoptosis is necessary for removing old cells and paving the way for the birth of new and healthier cells. Old cell materials are recycled and used as building blocks of new cells. However, some cells enter a state called senescence, where cell growth is arrested, and they no longer perform their functions. These senescent cells likewise do not die but continue to accumulate. Cellular senescence occurs as a response to various stressors that, include the following: 

  •  Hyperglycaemia 
  • Saturated lipids 
  • Increased reactive oxygen species (ROS) 
  • Oncogene activation 
  • Telomere shortening 
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Typically, senescent cells are removed by macrophages of the immune system. However, an imbalance in the destruction and production of these cells could increase the aging of nearby cells and tissues. Senescent cells release chemicals called senescence-associated secretory phenotype or SASP [4]. When senescent cells release SASP, which includes toxic chemicals and compounds, to the external environment, they would then inflict localised damage to healthy cells. The accumulation of senescent cells is associated with aging. As one gets older, the ability of the cells to remove toxic byproducts or to scavenge senescent cells is reduced. This explains why the accumulation of senescent cells becomes a vicious cycle. 

Studies conducted in recent years [5] revealed a strong association between the buildup of senescent cells and several age-related diseases and neurodegenerative diseases. Here are some conditions associated with senescence: 

  •  Cancer 
  • Vision loss 
  • Stroke 
  • Diabetes
  • Obesity 
  • Neurodegenerative disorders 
  • Emphysema 
  • Osteoarthritis 

Continuous accumulation of senescent cells can initiate early aging and increase the risk of developing chronic conditions. Removing the senescent cells could delay aging and promote overall health. In recent years, interest in senolytics has grown due to their ability to remove senescent cells. 

What are the factors that drive senescence? 

Several factors cause cellular senescence. Here are some examples: 

Oxidative stress 

Oxidative stress occurs when cells are exposed to excess reactive oxygen species (ROS). When present in appropriate amounts, reactive oxygen species are essential in regulating gene expression, cell proliferation, and the transmission of signals in the nerves. Reactive oxygen species are natural byproducts of oxygen metabolism in the body. However, when ROS are present in excess amounts, this can lead to cellular senescence. 

In healthy and younger organisms, ROS content is kept in appropriate amounts due to the presence of natural antioxidants in the body. These antioxidants, such as glutathione, scavenges excess ROS. However, as one age, the balance between ROS and antioxidants is disrupted. This imbalance damages macromolecules such as proteins, lipids, and DNA. 

Telomere shortening 

Telomeres are DNA-specialised structures that are highly repetitive and found at the ends of chromosomes. Research has shown that the length of the telomeres is associated with the lifespan of the cells. The length of telomeres is used as a predictor of cellular senescence. Shorter telomeres are associated with cellular senescence. 

Cell cycle inhibitors and tumour suppressors 

Several cell cycle inhibitors and suppressors have been identified in recent years. These inhibitors or suppressors could lead to early cellular senescence. 

One pathway that leads to cellular senescence involves damage to cellular DNA. In addition, shortening telomeres can trigger DNA damage response (DDR) in cells. Once DDR is activated, cells are prevented from entering the S or synthesis phase of the cell cycle. The S phase is necessary for preparing cells to undergo cell division and multiply. In addition, oxidative stress can also trigger a DDR in cells, leading to increased cellular senescence and damage [6]. 

Senolytics and current research 

Since senolytics target cellular senescence, an aging mechanism, it has broad potential to treat, prevent, or alleviate several age-related conditions. Importantly, senolytics can potentially treat multiple conditions simultaneously and not only individually. 

Senolytics drugs 

The first known senolytic drugs include quercetin (Q) and dasatinib (D) [7]. Dasatinib is a commonly prescribed chemotherapy drug for leukaemia patients, while Q is a pigment found in fruits and vegetables such as grapes, strawberries, onions, and red wine. The Q drug is a known anti-inflammatory drug used as an antioxidant that helps delay aging. When both D and Q are administered together, the combined actions of these drugs remove senescent cells. 

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Diabetes and senolytics 

Diabetes is recognised as one of the significant risk factors for premature aging or the development of age-related conditions such as renal dysfunction, cardiovascular disease, and cognitive impairment [4]. Cellular senescence is believed to play a crucial role in developing insulin resistance and associated complications of diabetes. When an individual has diabetes, this also leads to the increased formation of more senescent cells. Continuous exposure to high lipids and glucose levels can trigger cellular senescence [6]. 

Once senescent cells form, the toxic chemicals or SASP released by these cells also spread senescence to nearby and distant cells [6]. Through this mechanism, more cells enter senescence, which can trigger the onset of diabetes complications and other long-term conditions such as cardiovascular disease. 

Idiopathic pulmonary fibrosis and senolytics 

A small pilot study [8] conducted in 2014 revealed that patients with idiopathic pulmonary fibrosis (IPF), a debilitating and difficult-to-treat lung disease, who were treated with D and Q demonstrated improvements in their physical functioning. The study only recruited 14 volunteers, and findings could not be generalised to a larger and more heterogeneous group of IPF patients. However, the results were promising since these indicated that D and Q could potentially treat IPF by removing senescent cells. The findings offered preliminary data that could be verified in more extensive trials in the future. 

Diabetic kidney disease and senolytics 

Senolytics also have the potential to improve the physical functioning of patients with diabetic kidney disease. A small trial conducted by researchers from the Mayo Clinic [9] found that the administration of D+Q reduced senescent cells from the fatty tissue of the participants. Further, circulating SASP factors, the chemical that destroys nearby cells and tissues, were also reduced following D+Q therapy. 

The study was an open-label phase 1 pilot study. Findings could not be generalised to larger populations. However, additional trials examining the effects of D+Q on senescent cells of patients with diabetic kidney disease would help affirm the findings of this small trial. 

The study’s findings demonstrated that interventions targeting cellular senescence, one of the aging processes in humans, could prevent, delay, or alleviate multiple diseases associated with aging. Notably, the hypothesis that senolytics can target various age-related diseases in mice appears true. If the findings of small clinical trials (8,9) are verified in more extensive trials in the future, this would reveal another pathway to the treatment of age-related diseases and delaying aging. Increasing longevity or human lifespan might be within reach with promising senolytic drugs such as D+Q. 

Osteoarthritis and senolytics 

Osteoarthritis is an age-related disease where individuals experience loss of cartilage in joints. Individuals with osteoarthritis complain of extreme pain when walking. When this occurs, patients’ mobility is also affected. Older adults with osteoarthritis are often forced to reduce physical activities such as walking, which can harm their overall health. Hence, treating osteoarthritis or delaying the progression of this disease remains a priority for many healthcare practitioners. 

One of the primary cartilage cells in the joints includes cells called chondrocytes. These cells, as one age, undergo senescence. Current research [10] reports that these chondrocytes who experience senescence release high levels of SASP factors in the surrounding tissues of the joints. In turn, this can trigger senescence in otherwise healthy cells and tissues. Research [11] has shown that targeting these senescent cells and removing them from the tissues could help improve the joints’ health, relieve pain, and improve physical functioning. 

Currently, senolytic drugs called senomorphics are shown to target SASP factors released from senescent chondrocytes. This provided information that, in the future, senomorphics could be used to remove senescent chondrocytes and delay the progression of osteoarthritis. 

Atherosclerosis and senolytics 

Atherosclerosis is described as a condition where arteries in the human body have built-up fatty streaks, leading to occlusion of the blood vessel. Atherosclerosis or fatty deposits in the arteries supplying the muscles of the heart could lead to occlusion or blockage of the blood vessel. In turn, this would cut the blood supply to the heart muscle. When the blood supply occlusion is not sudden, the arteries create smaller channels called anastomosis. These anastomoses would help supply the heart muscles with oxygen and nutrients from the blood. However, when the occlusion is sudden, this can lead to a heart attack. Hence, it is necessary to treat atherosclerosis at the earliest possible time. 

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Three factors contribute to the development of atherosclerosis: 

  1. Presence of oxidised low-density lipoprotein in the blood vessel wall 
  2. Chronic inflammation 
  3. Malfunctioning vascular endothelial cells 

Vascular endothelial cells in coronary arteries that have atherosclerosis have been shown to release SASP factors, suggesting that these cells undergo senescence [11]. 

The presence of senescence in the coronary artery blood vessel cells would cause leakage in the endothelium. It also allows immune cells and macrophages to enter the endothelium or the blood vessels. Once the immune cells enter the walls of the blood vessels, they will degrade the walls of the blood vessels. The degradation of the walls will cause the oxidised LDL to be absorbed, becoming part of the fatty deposits. Hence, a vicious cycle is created when blood vessel walls are degraded. 

In addition, when SASP recruit macrophages and monocytes to the blood vessel wall, these immune system cells will undergo senescence, hastening the progression of atherosclerosis [11]. 

Senolytics are shown to be promising in treating atherosclerosis. Drugs with senomorphic properties include ruxolitinib and rapamycin. Both drugs inhibit mediators within the cells that lead to the production of SASP. By targeting the intracellular mediators, researchers believed that senescence is also delayed or stopped. 

Alzheimer’s disease and senolytics 

Alzheimer’s disease is a condition that affects mainly older adults worldwide. Although some younger individuals have early-onset dementia, this condition is more prevalent among older adults. Alzheimer’s disease is characterised by cognitive decline or impairment that progresses over time. Currently, there are several causes of Alzheimer’s disease. 

One of the defining characteristics of Alzheimer’s disease is the accumulation of amyloid-beta plaques. One of the protein aggregates found in senescent cells includes amyloid-beta plaques. One of the cells that naturally protect and maintain the blood-brain barrier has cells called astrocytes. When astrocytes become senescent, they release SASP, which limits the clearance of amyloid-beta plaques. When this occurs, more amyloid-beta plaques accumulate in the cells, leading to increased senescence and increased symptoms of Alzheimer’s disease. 

Longevity, or living for longer than the average life expectancy, is determined by different genetic, environmental and lifestyle factors.

The senolytic drugs dasatinib and quercetin have been shown in small human trials to control a crucial protein involved in SASP regulation effectively. When SASP production is reduced, this will help protect nearby cells from senescence and dysfunction. In turn, it is thought that this could delay the progression of Alzheimer’s disease. 

Cancer and senolytics 

Cancer is a condition that affects at least 17 million people each year and causes approximately 9.6 million death annually. This disease starts from a single cell that undergoes genetic mutations that affect its ability to increase and divide. When a cell has cancer mutations, it can divide indefinitely and proliferate. Cancer cells compete with other cells that are healthy for resources [12]. These cells outnumber healthy cells and can get the resources due to their mutations that favour the progression of the cell cycle [12]. 

Senescence has a critical role in the prevention of cancer. It should be noted that cancer cells must rapidly proliferate indefinitely. However, when cancer cells enter senescence, their ability to increase quickly and migrate to other body parts is curtailed. A stable cell cycle growth arrest would restrict the growth of the tumour and prevent further division of the cells. In addition, the SASP released by senescent cancer cells also adds to the anti-tumour activity of the cells and tissues [12]. 

Currently, chemotherapy is introduced to arrest the growth cycle of cancer cells. However, research has also shown that senescence can cause cancer proliferation due to its pro-tumorigenic activities. This could explain why patients can experience cancer relapse after chemotherapy [13]. Although this is a paradox in cancer research, many investigators believed that inducing senescence of cancer cells can arrest the spread and growth of these cells. 

One of the promising drugs used to induce senescence includes the drug Palbociclib. This drug selectively inhibits proteins that allow the proliferation of cancer cells. When these proteins are inhibited, this can lead to cell cycle arrest or senescence. Palbociclib is a promising treatment for breast cancer, melanoma, gastric cancer, hepatocellular carcinoma and liposarcoma. 

Frailty and senolytic drugs 

Older adults are at increased risk of frailty. Frailty is described as a clinical state where individuals experience a decline in physical, mental, or cognitive functioning. When older adults become frail, they are at increased risk of oxidative stress due to physiological aging. Many frail older adults suffer from general weakness, a decrease in muscle strength, unintentional weight loss, a decrease in walking speed and reports of exhaustion. Frail individuals would find it challenging to move around and perform activities of daily living such as bathing, eating or cleaning the house. 

According to researchers [14], frailty can result from cellular senescence. When frail individuals suffer from weakness and exhaustion, it is believed that this is due to systemic inflammation. When senescent cells begin to accumulate, this can result in the release of chemicals that alter the immune cells’ response. Alteration of the immune system’s response would eventually lead to systemic inflammation. Senolytics are thought to arrest senescent cells from releasing more toxic chemicals that would lead to aging and frailty. Targeting cellular senescence could help delay the progression of frailty or prevent this condition from happening. 

Progressive multiple sclerosis and senoyltics 

Multiple sclerosis is defined as an immune-mediated disease with no known direct cause. It is a chronic condition that is characterised by the loss of axons and neurons in the spinal cord and the brain. It also involves demyelination or destruction of the protective covering of neurons. 

Since multiple sclerosis affects the brain and the spinal cord, patients with this disease can exhibit numerous and varied signs and symptoms. Some of the symptoms include problems with balance, sensation, leg and arm movements, and vision. Although it can be occasionally mild, with some patients experiencing a relapse, it can be severe and lead to long-term disability. 

Here are additional symptoms of multiple sclerosis: 

  • Problems with thinking 
  • Muscle stiffness and spasms
  • Problems with coordination 
  • Numbness or tingling in different parts of the body 
  • Problems controlling the bladder 
  • Vision problems or blurred vision 
  • Difficulty walking 
  • Fatigue 

Although the exact mechanism of multiple sclerosis is not well understood, it is believed that cellular senescence could also play a role in developing this condition. Apart from the immune system attacking the myelin sheath of the nerves, it is thought that senescent glia and neurons accumulate in the brain. The SASP released from these senescent neurons and glia then cause inflammation of the surrounding structures and cells. 

Senolytics could play a neuroprotective role in multiple sclerosis. It is hypothesised that senotherapy could be applied to prevent senescence-associated chronic inflammation, promote remyelination, and prevent the loss of function of neurons. 

Sarcopenia and senolytics 

Sarcopenia is when muscle cells lose muscle mass and muscle strength. However, researchers have shown that muscle stem cells cannot indefinitely repair muscle tissue or differentiate into other types of muscle tissues. 

Muscle wasting is believed to be related to age, with older people at increased risk of sarcopenia or muscle wasting. Cellular senescence is thought to play a role in the development of sarcopenia. Senescent cells could up-regulate pathways and enzymes that lead to their destruction. 

Senolytics can treat and manage sarcopenia by targeting the pathways inside the cells that lead to cellular senescence. 

Non-alcoholic fatty liver disease 

Cirrhosis is a condition where the liver undergoes scarring. The scarring of the liver, also known as fibrosis and cirrhosis, could increase the risk of developing non-alcoholic fatty liver disease. Senolytics can prevent the development of non-alcoholic fatty liver disease by targeting mechanisms or cellular pathways that inhibit cellular senescence. 

Is it safe to use senolytics as a drug to increase lifespan? 

Current results from small trials and animal model studies are exciting. The benefits of senolytics have been observed in mice studies and small human population trials. Interestingly, no adverse effects or side effects were recorded in the small clinical trials. However, this does not mean that no adverse effects would be seen in more extensive trials. It is still too early to state if senolytics are safe in the long term. 

Although D+Q have senolytic properties, these drugs still need to be investigated in broader groups of populations to determine if these can be effective in treating several age-related diseases. 

More clinical trials could provide results on whether senolytics are safe for long-term use. Hence, waiting for safety data from more extensive and prolonged trials is necessary before taking senolytics. 

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[1] https://www.who.int/news-room/fact-sheets/detail/ageing-and-health  
[2] https://pubmed.ncbi.nlm.nih.gov/32686219/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117903
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234500/
[5] https://pubmed.ncbi.nlm.nih.gov/33328614/
[6] https://pubmed.ncbi.nlm.nih.gov/26106186/ 
[7] https://pubmed.ncbi.nlm.nih.gov/25754370/ 
[8] https://pubmed.ncbi.nlm.nih.gov/30616998/ 
[9] https://pubmed.ncbi.nlm.nih.gov/31542391/ 
[10] https://pubmed.ncbi.nlm.nih.gov/33208917/ 
[11] https://www.frontiersin.org/articles/10.3389/fragi.2022.866718/full#B11 
[12] https://pubmed.ncbi.nlm.nih.gov/29669859/ 
[13] https://pubmed.ncbi.nlm.nih.gov/27979832/ 
[14] https://pubmed.ncbi.nlm.nih.gov/26485647/ 

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