Cellular Senescence and Cognitive Decline: How Clearing Zombie-Like Cells Creates a Healthier Brain

Many people consider forgetfulness or a loss of memory to go hand-in-hand with increasing age — but does it have to be this way? With the ever-rising prevalence of cognitive-related conditions, ranging from mild memory loss to severe forms of dementia, researchers and patients alike hope to find new safe and effective treatments to reverse or prevent this age-related brain deterioration. Published in Aging Cell, a recent study from the Mayo Clinic adds to the evidence that one such treatment may soon be on the horizon.

The walking dead: how zombie cells contribute to aging

In this study, Ogrodnik and colleagues looked at how eliminating senescent cells from the body plays a role in slowing down or reversing brain aging. Simply put, senescence is when cells stop dividing and lose their function. This irreversible growth arrest occurs with increasing age or in response to various stressors, including inflammation and accumulation of reactive oxygen species — unstable compounds that cause oxidative stress, damaging cells and DNA.

Another factor that plays a role in cells becoming senescent is telomere length. Telomeres can be imagined as the plastic casing protecting the tip of a shoelace, as these repetitive strands of DNA “cap” the ends of our chromosomes. These endcaps protect the critical genetic information inside the chromosome from damage and dysfunction. Telomeres and cellular senescence go relatively hand in hand, as telomeres shorten with each cell division. When a cell reaches the end of its telomere, it can no longer replicate and is considered senescent.

However, while these senescent cells lose function, they don’t die. Instead of undergoing the routine and programmed cell death called apoptosis, senescent cells enter a “zombie-like” state that damages neighboring tissues and cells. This damage occurs through a feature called the senescence-associated secretory phenotype (SASP), which secretes a cascade of destructive compounds, including cytokines, chemokines, and growth factors. As a result, the inflammation and damage that comes along with cellular senescence are thought to contribute to age-related tissue and organ dysfunction and various chronic age-related diseases. 

Senescence and cognitive decline: a chicken-or-the-egg scenario

While all organs can be affected by an accumulation of senescent cells, the brain is especially vulnerable to the damage caused by these zombie-like cells and their associated inflammatory secretions. Previous research has found that clearing out senescent cells in mice improves various neurological conditions, including Alzheimer’s and Parkinson’s disease, and multiple sclerosis. However, we don’t yet know for sure which came first: does a buildup of senescent cells cause neurodegenerative diseases, or do neurodegenerative diseases lead to increased cellular senescence? 

Ogrodnik and colleagues aimed to uncover the answer to this chicken-or-the-egg question using different senolytics — compounds that can eliminate senescent cells from the body. They had two different approaches, using either the sole drug AP20187 (“AP”) or a senolytic cocktail commonly referred to as DQ, which is the combination of the chemotherapy drug dasatinib and quercetin (an antioxidant compound found in many fruits and vegetables).

While DQ is a non-specific senolytic with no single target, AP targets cells explicitly with high activation of p16Ink4a (p16). This protein accumulates in cells with age and is considered a biomarker of senescence. In this study, the research team predicted that using the non-specific combination of senolytics would be more effective at clearing out senescent cells than targeting one singular pathway, as not all senescent cells are characterized by high p16 levels. 

Taking a look inside aged mouse brains

While it’s known that senescent cells accumulate in the brain with age, researchers hadn’t yet pinpointed which types of brain cells are affected the most by this process. To elucidate this, Ogrodnik and colleagues first compared the cells and proteins that make up the hippocampus — the area of the brain responsible for learning and memory formation — between young, 4-month-old mice and aged 24-month-old mice (roughly representing humans in their 70s). 

The research team from the Mayo Clinic found that the aged mice had significantly increased p16 levels in non-neuronal cells called microglia and oligodendrocyte progenitor cells (OPCs). Microglial cells lead the immune response in the central nervous system (CNS), while OPCs support the growth of the protective sheath on nerve fibers called myelin. The aged mice also had increased activation and cell body size of their microglia, which occurs with inflammation and aging. While microglia are essential cells of the CNS, their overactivation is detrimental to brain health and contributes to neurodegenerative diseases.

The aged hippocampi also had markedly increased levels of pro-inflammatory compounds called cytokines, including one called interleukin-1ɑ (IL-1ɑ), an activator of SASP. Reducing IL-1ɑ levels could potentially slow down or prevent the inflammatory secretions that come from senescent cells. Lastly, older mice had increased levels of immune cells called T cells infiltrating the brain. Similar to microglia, T cells are beneficial and vital. But, they are associated with neurodegeneration when they permeate the brain, as SASP recruits these cells, and they can become senescence-associated T cells that promote inflammation.

The brain-boosting benefits of senolytics

Despite all of these detrimental age-related brain changes, senolytic therapies were able to mitigate most of the damage. In a second experiment, the researchers intermittently administered either AP or DQ for two months to young, 4-month-old mice and aged 25-29-month-old mice. Even though only AP specifically targets p16, both AP and DQ treatment led to significant reductions in microglial p16 levels, which then lessened microglial overactivation and SASP activity. Additionally, DQ treatment alleviated the T cell infiltration in the hippocampus and the high IL-1ɑ activity seen in the aged mice, further reducing SASP pathways.

These reversals of brain aging markers also translated to improved cognition and spatial memory — the ability to remember where an object is in relation to another. The two-month treatment of either AP or DQ significantly attenuated the cognitive decline that was seen with age. This was measured by the Stone T-maze, a test that relies on the brain’s navigational system to escape from shallow water. 

After AP or DQ treatment, the aged mice showed significant reductions in the number of errors made in the maze, although the time to complete the task remained unchanged. As senolytic treatment alleviated age-related cognitive decline, and the mice had excessive markers of senescence before developing dementia, these results add to the evidence that a buildup of senescent cells contributes to neurodegenerative disease and not the other way around.  "Our observations provide evidence suggesting that clearance of senescent cells may be a promising strategy to rejuvenate the aging brain," the authors propose.

Can DQ deliver in humans?

While the results of these senolytic treatments are promising in mice, there is limited data on the use of DQ for clearing senescent cells in humans, let alone in ameliorating cognitive impairment. One small clinical trial looked at the effects of intermittent and short-term DQ treatment in 14 patients with the highly fatal lung disease idiopathic pulmonary fibrosis (IPF). Although DQ did produce some mild to moderate adverse effects, including cough, shortness of breath, gastrointestinal discomfort, and heartburn, the senolytic treatment did improve several markers of physical function, which progressively deteriorates in IPF patients. “Our data provide proof‐of‐concept for senolytic interventions being a potential therapeutic avenue for alleviating age‐associated cognitive impairment,” concluded the authors.

Even though the low risk and high benefits of this particular trial are encouraging, more clinical trials with humans with different diseases — or naturally aged people — are needed to assess its safety and efficacy fully. Additionally, while the natural compound quercetin has shown brain-boosting potential in animal studies, human studies don’t always match the benefits. This discrepancy could be because quercetin has low absorption in the gut and may not fully penetrate through the highly selective blood-brain barrier that separates blood from the CNS.

So, solely taking quercetin on its own likely wouldn’t produce the same cognitive benefits seen in this animal study — the combination of the two is necessary. Despite the fact that both compounds are FDA-approved, dasatinib is currently only on the market for chemotherapy treatment with a prescription; not just anybody can go out and purchase it in the United States. For now, the only DQ you can buy at a store is Dairy Queen. 

References:

Amaya-Montoya M, Pérez-Londoño A, Guatibonza-García V, Vargas-Villanueva A, Mendivil CO. Adv Ther. 2020;37(4):1407-1424. 

Baker DJ, Wijshake T, Tchkonia T, et al. Nature. 2011;479(7372):232-236. Published 2011 Nov 2.

Justice JN, Nambiar AM, Tchkonia T, et al. EBioMedicine. 2019;40:554-563. Ogrodnik M, Evans SA, Fielder E, et al. Aging Cell. 2021;e13296. 

Zhang P, Kishimoto Y, Grammatikakis I, et al. Nat Neurosci. 2019;22(5):719-728.