Fight Aging!

Even given the point that the mouse models of age-related neurodegenerative conditions are largely very artificial, as mice do not naturally develop any form of pathology that resembles the most common human neurodegenerative conditions, there is compelling evidence for the accumulation of senescent cells in the brain to contribute meaningfully to the onset and progression of these diseases. Cells enter a state of senescence in response to damage, replicative stress, or environmental toxicity, among other causes. In youth such cells serve a useful purpose and are rapidly removed by the immune system. With aging the immune system becomes less efficient and as a result senescent cells linger and accumulate.

Neurodegenerative conditions have a strong inflammatory component, and senescent cells produce inflammatory signaling. The argument for targeting senescent cells to treat neurodegenerative conditions seems a straightforward enough proposition: more senescent cells in the brain means more inflammation and thus a worse prognosis for patients, a more rapid progression of neurodegeneration. Unfortunately, neurodegenerative conditions are not at present at the top of the very long list of conditions that might be treated by selective clearance of senescent cells using senolytic drugs. Academia and industry are largely focused on the role of cellular senescence in the aging of organs other than the brain, and so only the one small, exploratory clinical trial has taken place to test the senolytic combination of dasatinib and quercetin in Alzheimer's disease patients.

Cellular senescence: A novel therapeutic target for central nervous system diseases

Cellular senescence (CS), as a hallmark feature of aging, plays a crucial role in various aging-related diseases, including central nervous system (CNS) disorders. Research findings from cellular or animal disease models, along with detection data from human components, such as cerebrospinal fluid and brain tissue, provide compelling evidence supporting the close correlation between CS and CNS diseases. The transition of critical cellular components in the brain, such as microglia, astrocytes, and brain vascular endothelial cells, toward the senescent phenotype often triggers inflammatory cascades, disrupts the integrity of the blood-brain barrier, impairs neuroregeneration, and contributes to various pathological processes. This exacerbates neural damage, hampers tissue repair, and adversely affects prognosis.

Senescent cells (SCs), besides exhibiting a decline in normal structure and function, are intricately linked to the aberrant generation and accumulation of pathogenic substances, such as β-amyloid (Aβ), Tau protein, and α-Synuclein (α-Syn) in the brain, which contribute to prolonged and complicated conditions. Moreover, SCs can disrupt the balance of the local microenvironment through paracrine mechanisms, amplifying senescent effects and harming surrounding healthy cells. Notably, the development of CNS diseases involves molecular mechanisms that can induce CS. This process exacerbates neurotoxicity in SCs, creating a vicious cycle. Therefore, CS is a promising target for therapeutic intervention in CNS diseases, as disrupting the vicious cycle mediated by SCs in the brain has prospects for preventing and managing such conditions.

Recently, CS has become a prominent area of research in CNS diseases, especially neurodegenerative disorders. Clinical trials on senolytics in CNS disorders are limited. This is primarily because CS-based targeted therapy represents a relatively novel approach, and the diverse complexity of CNS diseases poses challenges in implementing and designing these methods. Further complicating matters is the unique structure of the blood-brain barrier, which limits the entry of many drugs into the brain to exert their effects while avoiding severe adverse effects. Only one study on Alzheimer's disease (AD) (NCT04063124) has published preliminary results. The trial recruited five patients with early AD symptoms for a 12-week intermittent anti-CS treatment (dasatinib and quercetin, D+Q). According to published data, both senolytic components D and Q levels are elevated in the blood. D was detected in the cerebrospinal fluid of four patients, while Q was not in any patient's cerebrospinal fluid. Notably, the team observed an increase in the expression of inflammatory cytokines in the participants' fluid. They speculated that this could be related to a transient trigger of inflammation when SCs are cleared or that it could serve as a marker of SC death.

While this early clinical study established that senolytic therapy is safe, feasible, and well tolerated in AD patients, effectively clearing amyloid-like proteins and reducing blood inflammation, a larger sample size and a placebo control group are required in future studies for further scientific validation. Trials NCT04685590 and NCT04785300 are advancing in this direction. These pioneering efforts to leverage senolytics for treating CNS diseases are highly anticipated.