Senolytics and dementia—The war against ageing


Are senolytics the answer to ageing? Image credit: Daniele Franchi, via Unsplash.

We all think about growing older. Whether seeing it in our loved ones or ourselves, many of us know how health issues increase with age. Ageing is a major risk factor for many diseases, including osteoarthritis, Parkinson’s, and Alzheimer’s. Therefore, our ageing population has increased healthcare needs, putting a strain on our health services. Much is being invested in the search for treatments that reduce these disease risks and improve the quality of human life in our later years.

During this research, scientists have highlighted the importance of senescent cells (SnCs) in age-related and chronic diseases. These cells are linked to almost all biological signs of ageing. Using senolytics—drugs that remove senescent cells from the body—may therefore alleviate the severity of disease symptoms. Notably, this manner of treatment, in which ageing itself is targeted, could be revolutionary in preventing the development of many age-related diseases in the first place.

What is senescence?

Senescence is a biological process in which a cell ages to the point that it stops dividing. Instead of dying and being removed, these cells lie dormant in the body. Due to unrepaired DNA damage, growth is paused in SnCs by a process known as “cell cycle arrest”. Identifiable by their flat and wide shape, SnCs accumulate with organism age, directly correlating with several age-related diseases.

While “normal” cells undergo a process of programmed cell death called apoptosis, SnCs are resistant to this mechanism. Either cell fate can be induced by cell stress or damage, but in severe cases, the cellular processes that lead to apoptosis are inhibited. Instead, to prevent the proliferation of damaged cells, affected cells become senescent. This irreversible change allows them to linger in tissues and cause inflammation, tissue dysfunction, and tumour development. SnCs also evade clearance by the immune system. This resistance stems from “SnC anti-apoptotic pathways” (SCAPs), which prevent the signalling events that cause apoptosis.

This manner of treatment, in which ageing itself is targeted, could be revolutionary in preventing the development of many age-related diseases in the first place.

Despite this, SnCs exist in mammals for a reason. When healthy cells reach their division capacity (known as the Hayflick Limit) and become genetically unstable, they are flagged for removal by the immune system. This mechanism blocks the abnormal and uncontrolled growth of cells, preventing cancer development. Hence, in their native capacity, SnCs prevent tumour formation. Considering this, complete inhibition of senescent cell formation would be detrimental to an organism.

The secretion of chemically reactive species and inflammatory mediators by dying SnCs induces something called a “senescence-associated secretory phenotype” (SASP). Molecules associated with SASP may induce senescence in neighbouring cells, perpetuating the effects of inflammation in a given tissue. SASP also exhibits systemic effects, which are associated with several age-related conditions.

What are senolytics?

Senolytics are a category of small-molecule drugs that target and eliminate SnCs. To do this, they interfere with SCAPs: the chemical pathways in cells that enable SnCs to linger. These drugs can help clear SnCs, and current research shows the potential to use senolytics in anti-ageing therapies. Scientists have demonstrated that mice treated with experimental senolytics exhibit healthier ageing and an extended lifespan. However, the dosages of these drugs have yet to be refined. In an ideal world, senolytics would improve ageing-related and disease symptoms with minimal side effects.

Research suggests that the most effective senolytics should target multiple senescent cell types and senescence-associated diseases. The ability to target multiple senescent cell types would allow for full-body therapies rather than treatments targeted to one place. Therefore, combining two or more senolytic drugs may be the best route to developing effective treatments.

Senolytic combination treatments

Many senolytics come from naturally occurring agents, such as the flavonol quercetin (Q). Flavonols are known for their anti-inflammatory, antioxidant, and antimicrobial properties, lending themselves to the treatment of overall health. Q is an antioxidant, aiding in the removal of compounds called reactive oxygen species (ROS) that naturally accumulate with age. When present in the body, excessive ROS can induce damage in important cellular molecules, such as DNA. As a result, a reduction in ROS can help to counter senescence.

The regular intake of molecules such as Q can help support a healthy lifestyle: Q can be found in various fruits, vegetables, and tea. However, the doses in food and drink are insufficient to have anti-ageing/anti-SnC effects due to the molecule’s low bioavailability. A substance’s bioavailability dictates its ease of entry into the bloodstream and, therefore, how much of a given dosage can reach its target. This means that when we, for example, eat an apple, very little Q within it would reach SnCs.

Many senolytics come from naturally occurring agents.

Combined with the molecule dasatinib (D)—a synthetic drug traditionally used to treat cancer—the SnC killing ability of Q is significantly increased. D targets and inhibits the activity of a particular class of proteins involved in cell survival. In this way, D works to drive SnCs to apoptosis. The improved effectiveness of the combined treatment suggests that combination target senolytic therapies may be more effective. However, the scale of this is still to be determined.

Alternatively, drugs used in cancer therapies (such as D) can be repurposed to target SnCs. The problem is specificity: the more targeted the therapeutic, the lower its toxicity and (likely) the better the treatment. However, many repurposed cancer drugs have several side effects, contrasting natural senolytics like Q, which have low toxicity profiles.

Senescence in Alzheimer’s

Age is a major risk factor for Alzheimer’s disease (AD). Due to our ageing population, the number of AD cases is on the rise, and therefore the search for effective treatments is imperative. In this neurodegenerative disorder, a patient’s cognition declines with age, which is believed to be due to the accumulation of two proteins: tau and amyloid-beta. Physiologically, tau protein stabilises the internal skeleton of neurons, which helps to maintain cell integrity. In AD cases, however, the protein assembles into insoluble filaments inside neural cells, causing aggregates known as “neurofibrillary tangles”. Amyloid-beta is also naturally occurring and is believed to improve memory in the healthy population. Upon accumulation, however, the protein forms large plaques that disrupt essential connections between neurons.

The primary affected cells when considering senescence in AD are glial cells. These cells are key in modulating inflammation of the brain and the integrity of the protective barrier around the brain. Interestingly, these are also the only neural cells susceptible to DNA damage known as telomere shortening. Telomeres act as a protective cap on coding DNA. A natural shortening process occurs throughout a cell’s dividing life: each time it divides, its telomeres are cut away until the protective cap is gone, and a cell reaches the Hayflick Limit. As with other SnCs, senescent glial cells upregulate the secretion of certain proteins/small molecules that are associated with AD. These secretions are mediated by changes in glial cell gene expression, which may provide a tantalising new target for senescent glial cell removal or prevention. Notably, the clearance of senescent glial cells reduces brain pathology in an AD mouse model.

The issue with senolytics

Ageing itself is not considered a disease. Instead, advancing age increases the likelihood of other diseases. The implication of this is that drugs to combat ageing, such as senolytics, are often not prioritised for further investigation in clinical trials. As a result, there is still a lot that we don’t know about senolytic therapies.

Since Q can be bought readily without a prescription, there is a serious risk of senolytic overconsumption. In recent years, “wellness” culture has grown in popularity. It is important to note that this is both a social and scientific issue since, for centuries, ageing has been seen as “undesirable”. Many are on the hunt for an anti-ageing fix. Therefore, knowledge about the potential anti-ageing effects of senolytics could lead to abuse and cause devastating effects.

Hearing about senolytics in the news has given people hope for a cure to combat ageing, feeding this desire for youth. Now, people are endeavouring to take senolytics from over-the-counter sources for anti-ageing effects without considering that many of these drugs have not been adequately tested in humans. Furthermore, when one takes a drug unnecessarily, there is a risk of side effects and of developing health complications.

The future of senolytics

Combining senolytic treatments with other anti-ageing measures may prove the most effective against variable ageing processes. Therefore, by targeting ageing processes rather than any one chronic disease, treatments may have a greater influence on improving the quality of life for the ageing population. The research surrounding senolytic use in AD is looks positive, showing promise for the future treatment of AD patients. While there are issues surrounding senolytic use and production, the development of these treatments may help us all in the journey towards healthier, longer lives.