James Kirkland, MD, PhD, and his Mayo Clinic team are spearheading research that aims to prevent or reverse multiple diseases of aging.

Compounds known as senolytics are being tested in 16 clinical (human) trials.¹

Early evidence suggests they may do more than target chronic diseases. They may also counteract certain aging processes.

Dr. Kirkland, along with a growing number of scientists, believes the body’s accumulation of senescent cells is a critical factor in disease, frailty, and aging.

His research is focused on identifying and testing agents that safely remove these toxic, old cells.

In the August 2022 issue of Nature Medicine, Dr. Kirkland and two colleagues note that senescent cells are a target for “disorders across the lifespan.”²

Senescent Cells

Ideally, old cells begin a programmed sequence of self-destruction, known as apoptosis, and are cleared away by the immune system.

But senescent cells behave differently. They don’t self-destruct.

Instead, they linger and emit a toxic mix of protein-degrading enzymes that damage healthy cells. They also secrete pro-inflammatory factors that contribute to chronic low-grade inflammation.³

Dr. Kirkland attributes the accumulation of senescent cells to be causative factors of degenerative aging and chronic diseases.

These senescent cells are what Dr. Kirkland and others seek to safely eliminate.

Dangers of Senescence

The idea that removing senescent cells could boost longevity was based partly on the observation that mice with mutations that increase lifespan have fewer senescent cells than normal mice. Similarly, very short-lived mice have more senescent cells.⁴

In studies in some human cell and animal models, removing senescent cells from the body improves markers of aging and prolongs lifespan.^5-9

Senescent cells also increase in a number of chronic diseases.⁶

Dr. Kirkland and his collaborators are investigating the effects of eliminating senescent cells in models of Alzheimer’s disease, arthritis, osteoporosis, frailty, and other disorders.

Senolytics

Compounds called senolytics have the capacity to safely sweep away senescent cells.^9,10

They work by reactivating the apoptosis switch in senescent cells, causing these toxic cells to die off, and provide room for healthy, functioning cells.

Dr. Kirkland has worked intensively on the potential for senolytics to reverse a range of chronic diseases and increase human longevity.

Senolytics being tested include the anticancer drug dasatinib, the plant-based nutrients quercetin, theaflavins, and fisetin, and a growing list of related compounds.

The senolytic effects of these compounds have been documented in rodents and human cultured cells.

Compared to untreated mice, those that started a dasatinib-quercetin mix at an age equivalent to 75 to 90 years in humans ended up living about 36% longer, with better physical function.¹¹

Senolytics have effectively prevented, delayed, or alleviated a variety of conditions and diseases in mice.

Clinical trials currently underway for senescence-related diseases have shown early but clear signs of promise.

In humans, a brief course of senolytics enhanced several measures of physical activity in patients with idiopathic pulmonary fibrosis, a progressive lung disease.¹²

Daunting Roadblocks

Human trials of senolytics could change medicine forever. They could allow us to switch from treating symptoms to circumventing root causes of aging and age-related disease.

Of course, these trials can take many years, given the timeframe needed to observe a significant change in longevity.

Lack of funding delayed getting senolytic trials started. As Dr. Kirkland noted in the review of which he was a co-author, companies and entrepreneurs are generally uninterested in funding studies of nutrients or existing drugs because they’re unable to patent them.²

Even more daunting, bureaucratic mandates and regulatory red tape are proving to be the greatest roadblock.

In a recent interview, Dr. Kirkland described the voluminous paperwork and endless regulatory hoops holding his team back.

Dr. Kirkland and his team wanted to study the plant compound fisetin, known to be a promising senolytic. Before getting approval, however, the U.S. Food and Drug Administration (FDA) forced them to compile a highly technical, 450-page Independent New Drug report on fisetin.

Preparing this one document for FDA submission required 2.5 years.

These roadblocks were erected despite over 5,000 Americans a day perishing from an age-related pathology.

Summary

Senescent cells are a major cause of accelerated aging and the development of chronic age-related disorders.

The research into senolytics by Dr. Kirkland and his colleagues seek to delay the onset of multiple degenerative illnesses and increase healthy human lifespans.

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References

1. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=senolytic&cntry=&state=&city=&dist=. Accessed September 7, 2022.
2. Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022 Aug;28(8):1556-68.
3. Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol. 2021;9:645593.
4. Available at: https://www.mayo.edu/research/faculty/kirkland-james-l-m-d-ph-d/bio-00096544. Accessed September 1, 2022.
5. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58.
6. Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017 Jul;21:21-8.
7. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6.
8. Jeon OH, Kim C, Laberge RM, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017 Jun;23(6):775-81.
9. Kirkland JL, Tchkonia T, Zhu Y, et al. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. 2017 Oct;65(10):2297-301.
10. Malavolta M, Bracci M, Santarelli L, et al. Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy. Mediators Inflamm. 2018;2018:4159013.
11. Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018 Aug;24(8):1246-56.
12. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-63.