Aging is a natural process observed in several biological species, including humans. The mechanism of aging is multifactorial and characterized by multiple degenerative processes. These changes result from various alterations in molecular pathways. The molecular changes impair the full functionality of cells and tissues. Due to its numerous physiological effects, aging is the leading etiological factor for several diseases, including cardiovascular diseases, neurological disorders, cancers, diabetes, and other systemic conditions. The prevalence and impact of aging-related diseases are increasing globally.
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Scientists involved in aging research have sought to identify the underlying mechanisms of aging, explore ways to delay its onset, and develop therapeutic strategies to slow its progression. Cellular senescence is recognized as one of the major contributors to aging and age-related diseases. It is a process characterized by the irreversible arrest of cell proliferation in response to various stressors. Some current therapeutic interventions aimed at promoting healthy aging are focused on targeting cellular senescence. The development of senolytic drugs, which selectively eliminate senescent cells, has become a major area of interest in aging research. These agents have the potential to improve tissue function and reduce the burden of senescent cells. This therapeutic approach aims to enhance tissue regeneration and preserve physiological function during aging. Among the most studied senolytic agents are dasatinib and quercetin. These compounds have been investigated for their potential benefits in reducing cellular senescence, improving tissue health, alleviating fibrotic diseases such as idiopathic pulmonary fibrosis, and improving physical function, as demonstrated in some animal models and early human studies.
Although a greater number of research studies have focused on mouse models, some anti-aging studies have investigated the combined effects of these senolytic agents in human subjects. These findings suggest a potential therapeutic benefit for addressing aging in humans.
Combining Dasatinib and Quercetin for anti-aging effects
Cellular senescence refers to the permanent loss of a cell’s ability to proliferate, usually in response to stress or damage. Various lines of research evidence show that chronological aging increases the burden of senescent cells. Therapeutic management with senolytic drugs in aged mouse models has demonstrated a reduction in aging-associated functional declines. Although reversing biological aging in humans remains scientifically challenging, the combination of dasatinib and quercetin has shown evidence of being a safe and potentially effective option for improving aging-associated changes. Recent findings indicate that this drug combination may reduce the accumulation of senescent cells and lower the risk of age-related diseases.
The accumulation of senescent cells is associated with functional decline in multiple tissues and organs. Although senescent cells remain metabolically active, they often acquire tissue-destructive and pro-inflammatory traits, while simultaneously exhibiting resistance to apoptosis.
Senescent cells produce factors that contribute to inflammation and tissue dysfunction. These cells accumulate with age. Senolytics are drugs that selectively target and eliminate senescent cells by inducing apoptosis, without affecting non-senescent cells. The ability to delay the accumulation of senescent cells has the potential to extend healthy lifespan and reduce the incidence of age-related diseases.
The first senolytic drugs discovered were dasatinib and quercetin. They were identified using a mechanism-based approach, targeting known vulnerabilities in senescent cells rather than through random high-throughput screening. Although this method focused on specific senescence-associated mechanisms, subsequent studies have explored combination therapies. Dasatinib and quercetin affect several molecular pathways, including tyrosine kinase signaling and PI3K pathways, although the full spectrum of their effects continues to be investigated.
Although this combination of drugs has not been approved for use in the general population as an anti-aging treatment, prospective clinical studies have evaluated the effectiveness of the combination on the epigenetic aging rate of study participants. Early results suggest that this drug combination may have therapeutic potential in decelerating biological aging and promoting healthy longevity.
Mechanisms of action
Various senolytics, including the combination of dasatinib and quercetin, can selectively eliminate senescent cells as they accumulate with age. The mechanism of action for these drugs involves transiently disabling the survival pathways that protect senescent cells from undergoing apoptosis.
These drugs act independently and have some limitations. For example, dasatinib does not effectively target senescent endothelial cells in humans, and quercetin does not efficiently eliminate senescent human adipocyte progenitors. To overcome these limitations, researchers combined both drugs to broaden the range of senescent cell types targeted.
Several studies suggest that eliminating up to 30% of senescent cells can significantly reduce age-related dysfunction. Thus, the combination of these two senolytic agents has been shown to be effective in this regard. The drug combination is typically administered intermittently rather than continuously due to the short half-lives of both agents.
The first human trial using the dasatinib and quercetin combination demonstrated a significant improvement in physical function among subjects with diseases driven by cellular senescence. These findings highlighted the potential application of this drug combination in mitigating aging-related decline.
Unlike conventional drugs that require continuous presence in the circulation to occupy receptors, modulate enzymes, or affect biochemical pathways, senolytics target senescent cells directly. Therefore, intermittent administration of senolytics effectively minimizes potential off-target effects associated with continuous receptor or enzyme modulation, at least as demonstrated in mouse models.
Dosage
There is currently no clinical consensus on the recommended dosage of senotherapeutics. Different studies have used varying dosages depending on their study design. One study administered a combination of 100 mg of dasatinib and 500 mg of quercetin daily for three consecutive days, reporting a decrease in senescent cell markers. Another study utilized 50 mg of dasatinib and 500 mg of quercetin for three consecutive days each month over six months, observing slower senescent cell accumulation and reduced markers of biological aging. More clinical research is necessary to determine population-specific dosing regimens that maximize anti-aging benefits while minimizing side effects.
Quercetin. Credit: Swanson
Cost
Dasatinib and quercetin stand out because they are already available for purchase. Senolytic therapy is intended to be administered intermittently, typically once every few months, as it eliminates existing senescent cells, and repeating treatment too soon would be unnecessary until enough new senescent cells have accumulated. Quercetin, a widely available supplement, usually costs less than a dollar per treatment, although depending on the manufacturer and quality, prices can reach up to $35.
Dasatinib is sold by manufacturers at prices ranging from $20 to $150 per dose appropriate for senolytic therapy. Sprycel, the FDA-approved version of dasatinib, costs between $300 and $600 for the same amount when adjusted by dividing a full bottle of tablets. However, Sprycel may be obtained for lower prices when purchased from international sources outside the United States.
If this pharmaceutical combination proves effective as an anti-aging intervention in humans, it would likely remain affordable for a sizable portion of the global population, assuming prices do not increase significantly. Nevertheless, dasatinib and quercetin are not the only candidate senolytic drugs being explored.
Both dasatinib and quercetin are available for purchase online through platforms like Amazon and can be shipped to many parts of the world. Retail pharmacies also carry these drugs, although availability and pricing may vary by location.
Risk
The combination of Dasatibin and Quercetin has only been applied in controlled clinical trials. Hence, it is difficult to show its risks and side effects at the population level. In the drug trials, there were no significant risks reported. The combination proved to be effective in eliminating senescent cells in various tissues.
Senolytics have been shown in pre-clinical studies in mice to delay, prevent, or alleviate a variety of age and senescence-related conditions. These conditions include frailty, cataracts, age-related osteoporosis, age-related muscle loss, radiation-induced damage, cardiac dysfunction, vascular dysfunction and calcification, pulmonary fibrosis, hepatic steatosis, metabolic syndrome, diabetes, and dementia. Overall, senolytic agents and the elimination of senescent cells have been shown in mice to improve physical function and extend health span and lifespan.
The findings of the first-in-human, single-arm, open-label clinical trial of senolytics were published in 2019. Subjects with idiopathic pulmonary fibrosis, a fatal disease caused by cellular senescence, showed significantly improved walking endurance, gait speed, chair rise test performance, and Short Physical Performance Battery scores five days after nine doses of a combination treatment with Dasatinib and Quercetin.
Conclusion
The combination of dasatinib and quercetin shows real potential for improving healthspan and extending survival as we age. Since senescent cells are known to drive much of the decline associated with aging, these two senolytics offer a promising way to slow that process. If ongoing research confirms their safety and effectiveness, longer, healthier lives could become more achievable for a broader population. For now, the combination is still being tested in controlled clinical trials, with no major serious adverse events reported so far. Beyond extending lifespan, this approach may also help reduce many of the chronic conditions that come with aging. With growing evidence of its ability to improve physical function and overall health, researchers see this therapy as a possible major step forward in the science of aging.
References
TruDiagnostic. (2021, August 3). Safety and effectiveness of quercetin & dasatinib on epigenetic aging (ClinicalTrials.gov Identifier: NCT04946383). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04946383
Novais, E.J., Tran, V.A., Johnston, S.N. et al. Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat Commun 12, 5213 (2021). https://doi.org/10.1038/s41467-021-25453-2
Saccon, T. D., Nagpal, R., Yadav, H., Cavalcante, M. B., Nunes, A. D. C., Schneider, A., Gesing, A., Hughes, B., Yousefzadeh, M., Tchkonia, T., Kirkland, J. L., Niedernhofer, L. J., Robbins, P. D., & Masternak, M. M. (2021). Senolytic combination of dasatinib and quercetin alleviates intestinal senescence and inflammation and modulates the gut microbiome in aged mice. The Journals of Gerontology: Series A, 76(11), 1895–1905. https://doi.org/10.1093/gerona/glab002
