New Longevity Initiative: How Cancer Drugs Decelerate Aging

Longevity Research Significance

Longevity research examines how we can live longer, healthier lives free from disease. In other words, it seeks to boost healthy aging and increase our healthspan, not just our lifespan. It does this by analyzing the hallmarks of aging, such as DNA damage or mitochondrial dysfunction, and understanding ways we can reverse it. These approaches are intertwined with various other research disciplines, like stem cell biology, and lifestyle factors, such as eating habits.

Rapalink-1 Experiment on TOR Pathway

One of the newest advances in longevity research has been the association between cancer drugs and aging. Researchers at Queen Mary University of London’s School of Biological and Behavioural Sciences have examined this link by conducting a study on fission yeast, a simple organism widely used in biological aging research. There, they studied how Rapalink-1, which is a third-generation drug used in cancer therapy, can affect the yeast’s lifespan. Rapalink-1 works by inhibiting the dysregulation of the target of rapamycin (TOR), which is present in both humans and yeast.

Under normal circumstances, TOR is a signaling pathway that is responsible for cell metabolism, growth, proliferation, and survival. However, when cell division is uncontrolled, leading to mistakes in DNA, mutations can form and disrupt TOR’s normal functioning. More specifically, the dysregulation occurs in the TOR Complex 1 (TORC1) pathway. TORC1 acts as a central hub that determines whether cells grow based on environmental conditions. Simply put, the environment is helping to decide which pathways turn on or off in TOR. When TORC1 is not working properly, this can lead to the formation of tumors and subsequent cancer metastasis.

In their study, the researchers found that Rapalink-1 did indeed slow down certain aspects of the yeast’s cell growth, while simultaneously extending their lifespan by inhibiting the TORC1 pathway. Rapalink-1 does this by functioning as a metabolic feedback loop involving agmatinase. Agmatinase is an enzyme that breaks down agmatine (i.e., a biogenic amine made by gut bacteria) into polyamines. Polyamines are essential organic molecules composed of multiple amino groups; one example of them is putrescine. At optimal levels, putrescine positively contributes to longevity, as it helps to maintain healthy TOR activity. Nevertheless, when agmatinase cannot successfully break down agmatine, yeast cells grow at a rapid rate and show premature signs of aging. This demonstrates how there is a trade-off between cellular growth and cell survival, as the faster the cells grow, the quicker the organism will age over time.

Converting Laboratory Findings Into Clinical Applications

Since agmatine is derived from diet and gut microbiomes, scientists can further identify how diet impacts aging through this research. This is because aging does not solely rely on our biology and genetics to begin its degeneration process. Contributing factors to aging include other psychosocial factors that influence our health and well-being, such as what foods we consume, our mental health, the environments we live in, our exercise levels, what recreational activities we partake in, and the amount of sleep we get per night. Depending on how we take care of these lifestyle factors, they will either accelerate or decelerate the aging process in tandem with our genetic predispositions.

Despite such optimistic findings, the current research we have is still far away from us being able to recommend agmatine supplements. This is because we do not have enough data to demonstrate its effectiveness for longevity and cellular growth for human beings. While agmatine does hold promising benefits, scientists believe this can only happen when certain metabolic pathways are intact. This may not always be the case, as aging is a driving force for cellular degradation. Additionally, agmatine has actually been reported to be connected to different disease pathogenesis, meaning it is not always beneficial for preventing illnesses. Therefore, with all that being said, science still needs to investigate how this research can translate from bench-to-bedside conclusions.

Senolytics Response to Senescence

Another class of cancer therapy drugs that are connected with longevity properties are senolytics. Senolytics rejuvenate damaged tissues and physiological function by selectively clearing out senescent cells, which are cells that have exited the cell cycle and are permanently stuck in the G0 phase, meaning they are no longer dividing and replicating.

Senescence is a hallmark of aging that occurs due to cellular damage and stress. It typically occurs with advanced aging, as that is when we usually experience telomere length erosion. When telomeres, which are protein cap complexes at the ends of a chromosome that protect the genetic material inside, naturally shrink from repeated cell division, senescence is triggered. This process is known as the Hayflick limit, which refers to how many times a cell can divide before it enters senescence. As a result of this erosion, the cell’s DNA is exposed and susceptible to damage over time. Senescence relates to cancer because senescent cells resist apoptosis (i.e., programmed cell death), allowing cancerous cells to persist and influence tumor development.

Senolytics gained a lot of recognition for their ability to prolong the onset of chronic diseases related to aging and subsequently extend the lifespan. Such information is valuable to longevity research efforts, as scientists predict that, by 2050, US adults who are 50+ years old and have multiple chronic diseases will increase by more than 90%. This means that approximately 15 million people are projected to be affected by this growing phenomenon.

Dasatinib and Quercetin

Two senolytics that are linked with aging and cancer therapy are Dasatinib and Quercetin. The combination of these two compounds is widely used in clinical trials and drug therapies, as they are able to induce apoptosis in senescent cells rather than solely help with managing symptoms. Previous studies with aged mice have demonstrated their effectiveness by extending the lifespan and healthspan, leading scientists to analyze senolytics with great interest.

Dasatinib is an FDA-approved drug commonly used to treat myeloid leukemia. It also has potential anti-diabetic properties, but that is still up for investigation. Dasatinib is a tyrosine kinase inhibitor (TKI), meaning it inhibits this enzyme when it works improperly. If not stopped in time, dysregulated TKs are associated with irregular cell division and the development of various cancers, such as non-small cell lung cancer. Dasatinib is able to do this with the help of quercetin, a polyphenol (i.e., antioxidant).

Unlike Dasatinib, Quercetin is a nutrient naturally found in a variety of foods, including Chinese herbal formulas, plants (e.g., onions), and fruits (e.g., berries and apples). It functions similarly to Dasatinib by inducing apoptosis in senescent cells. Aside from its biological benefits, Quercetin also has positive psychological influences. For example, it has been known to increase the production of norepinephrine, serotonin, and dopamine, which are neurotransmitters known for making us feel good. This means that quercetin can assist with other chronic illnesses that are comorbid with cancer and aging, such as depression. Such findings are really integral within this field, as it means that something as simple as food is able to decelerate aging and improve mental health. It also highlights a point made earlier about how complex aging is and how we should study it through a biopsychosocial lens.

Senotherapeutic Limitations

Although this research provides great insight into the field of longevity, it still has some drawbacks. One major one is that science is still not able to decipher whether a cell has permanently (i.e., senescence) or temporarily (i.e., quiescent) stopped dividing. This means that our current understanding is not yet equipped to make this distinction and identify which exact cells we are supposed to target.

This gap in our understanding is further emphasized when we consider how we still do not have the proper equipment to locate where senescent cells are across different tissues and diseases. We need to consider this, as it is crucial that we do not eliminate all senescent cells in the body. Under short-lived and controlled environments, senescence can be helpful for various processes, such as acute wound healing by assisting with tissue remodeling. The problem arises when senescent cells are still present for longer periods of time, provoking biological degradation.

Another limitation is that senolytics actually decrease the length of telomeres, not add to them. In one study, telomere length in mice was reduced by 17% after they were given Dasatinib and Quercetin. Scientists hypothesize this may be because the process of clearing out senescent cells through senolytics might require existing healthy cells to continue dividing, further shortening their telomere length. Even though this shrinkage is reported to not result in drastically short telomeres and telomere dysfunction, it is still worth noting, as its erosion is associated with aging. Overall, as science progresses, we may eventually be able to translate these findings into human models to further investigate their effects and potentially live in a world where our healthspan is increased.

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