Cellular senescence is one the nine hallmarks of aging. Our cells replicate and divide as part of the normal cycle of tissue repair and maintenance, but as they go through this process a large number of times some cells can eventually enter what is called a stable cell cycle arrest: the cell stops growing and replicating but doesn’t die, it just hangs around.
There are several drivers that are known to have a causal link with senescence. One of the first to be identified was the shortening of telomeres, the protective caps and the ends of our DNA strands. As cells replicate and split, telomeres tend to shorten and can getdegraded to the point where they can no longer protect against DNA replication errors. In response, the cell stops dividing and becomes senescent in order to prevent the replication and spread of damaged DNA. The other primary drivers of senescence include epigenetic dysregulation, mitochondrial dysfunction, and other types of DNA damage.
Senescence as a central hallmark of aging: drivers and effects
What happens next, is what makes senescent cells a likely driver of cellular aging. Senescent cells show clear alterations in metabolic activity and undergo dramatic changes in gene expression. They also develop a complex senescence-associated secretory phenotype that is thought to trigger senescence in healthy cells, even if they are not in close proximity. The presence of senescent cells has been shown to accelerate aging processes such as chronic inflammation, stem cell exhaustion, nutrient signaling dysfunction and proteostatic dysregulation.
Much of what we know about the effects of senescence on cellular aging comes from the research of Dr. James Kirkland. He is the Director of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic in Minnesota where he has worked since 2007, as both a practicing geriatrician and a prodigious researcher. Dr. Kirkland has authored over 200 scientific papers and has in many ways led the charge in expanding our understanding of the underlying mechanisms driving senescence and how to counter its effects.
The arc of Kirkland’s career is a great way to understand the evolution of senescence research. He first became intrigued about senescence early in the process of conducting research for his PhD when he came across the work of Leonard Hayflick who was the first scientist to discover the existence of senescence in cell cultures. Until then, scientists believed cells could continue dividing indefinitely. Hayflick’s findings proved that not to be the case, raising the possibility that aging could be happening at the level of the cell and not at just at the level of the organism as had been the thinking until then. These discoveries led Kirkland to become particularly curious about understanding the causes of senescence in cells.
Kirkland’s research was further inspired by a 2004 paper by Nornan Sharpless that showed that the rate of accumulation of senescent cells in mice could be slowed down through the use of healthspan extension tactics like caloric restriction. This finding made Kirkland wonder if the presence of senescent cells might be not a by-product of aging but actually a driver of some aspects of the aging process.
The pursuit of an answer to this question led to years of research during which Kirklanad and his team cycled through a number of different approaches to identify compounds that could specifically target and eliminate senescent cells without affecting healthy cells around them. What Kirkland was trying to find out was the effect that getting rid of zombie cells could have on the overall aging process.
First proof of the use of senolytic compounds
These efforts eventually resulted in the 2015 publication in Aging Cell of the seminal study that opened the floodgates of interest in the field of senolytics we see today. This research showed for the first time that senescent cells could be effectively targeted. Building on research that useda transgenic suicide geneto kill senescent cells in mice, Dr. Kirkland and his team used small interfering RNA (siRNA) to silence the expression of key components in two pathways that the team discovered senescent cells use to survive even as they kill the cells around them. The objective was to selectively kill the senescent cells by deactivating these pathways while leaving healthy cells unharmed.
To target the cells, Kirkland's team used the first two senolytic compounds they identified—dasatinibandquercetin— using a data-driven screening approach. The study, based on a mice model, showed that the combination of both compoundsreduced the senescent cell burden in old mice and improved theircardiac function and carotid vascular reactivityfollowing a single dose. These compounds alsoimproved exercise capacity for 7 months in mice that were subjected to irradiation of a single limb.
Additionally, periodic administration of the senolytics extended healthspan and delayed age-related disability and disease pathology in mice. Results in human cells suggested that the drug dasatinib eliminates senescent fat cells, while quercetin killed senescent endothelial cells. In other words different types of senolytics kill different types of senescent cells.
The results of this study were the first of their kind to show how to take out the survival pathways in senescent cells to induce their death without causing harm to healthy cells. Besidesdasatinib and quercetin, Kirkland's research team identified a total of20 compounds with senolytic potential that are currently being studied. More importantly, the design and results of this study served as a springboard for other aging researchers to discover senolytic compounds, which now number close to 100.
Senolytics Have the Potential to Delay the Onset of Age-Related Disease
Kirkland and his team followed up with another set of very successful trials published In this 2018 paper titled “Senolytics Improve Physical Function and Increase Lifespan in Old Age.”
Through a set of experiments the research team showed that senolytics can be used to delay the onset of nearlyall age-related diseases in mice. In this study, Dr. Kirkland and his team set out to examine two things: 1) whether clearing senescent cells with senolytic drugs would delay age-related diseases, and 2) whether transplanting senescent cells into younger mice could cause age-related diseases.
To test their first question, study authors treated two cohorts—naturally aged mice and young mice that had been injected with senescent cells—with senolytic compounds. Results of this phase of the experiment showed that treating aged mice with senolytic drugs resulted in increased lifespan and delayed onset of all age-related disease. Results also showed that treating the mice that had senescent cells transplanted with senolytic drugs delayed the onset of disease and early death.
To test the second hypothesis and establish that senescence accelerates aging, the study authors split young mice cohorts into two groups, injecting control mice with non-senescent cells and injecting experimental mice with senescent cells at a ratio of 1:10,000. After tagging the transplanted cells with a label, the results of the study showed that injecting mice with a million senescent cells caused them to die earlier of age-related diseases when compared to controls. Authors also found that senescence spreads to different tissues when the number of senescent cells in an organism exceeds the rate at which the immune system can clear the cells.
The results of this study demonstrate the potential of senolytics to revolutionize the way we approach aging. Senolytic drugs don’t adhere to the “one drug one disease” hypothesis; instead they are able to address multiple diseases by targeting one specific type of cell and disrupting key pathways that senescent cells require for survival.
Go Deeper: Read more of Dr. Kirkland’s key studies
- Senolytics Decrease Senescent Cells in Humans
- Senolytics Prevent Inflammation and Promote the Survival of Aged Organs
- The Clinical Potential of Senolytic Drugs
- Targeting Senescent Cells Alleviates Obesity-induced Metabolic Dysfunction
Not yet ready for prime time?
Despite the promising results that preliminary studies of senolytics have shown, Dr. Kirkland believes that senolytic compounds have yet to meet the rigorous safety standards needed for use in human subjects. Since senescence is a fundamental cellular process, we simply don’t know enough yet to understand the risk of interfering with it. The research is advancing very rapidly and much of it is too new to be able to make confident decisions about safety.
Understandably, Dr. Kirkland prefers to err on the side of caution and thinks it is not advisable for anyone to begin using senolytics outside of the lab. The good news is that a lot of progress is being made.. There are currently at least 12 senolytic drugs being investigated in human trials for safety, efficacy, and tolerability. Most of these studies are focused on addressing serious life-threatening disease conditions for which there are no viable treatments or cures. For people with this risk profile, using senolytics might be a clearer tradeoff.
No doubt the pace of research in this space will continue to accelerate and with it our understanding of how we can best incorporate senolytics into anyone’s longevity protocol.
In the meantime, some longevity hackers have been experimenting with natural compounds with senolytic qualities and good safety profiles such as fisetin and quercetin. These are also the main ingredients of a number of senolytic formulas we found:
- Life ExtensionSenolytic Activator ($20)
- SuperSmartSenolytic Complex($69)
- RestoreLife Formulas Senolytic Renew Supplement ($40)
- Alive By Science FisetinLiposomal Sublingual Gel ($65)
Since there is no way to easily measure if a senolytics like fisetin or quercetin are actually working to reduce your burden of senescent cells, deciding to experiment with these natural compounds becomes a very personal decision that should be made with the advice of your health coach or primary care doctor.
The Future of Senolytics and Aging
Senolytics have shown great potential when it comes to combating aging and age-related diseases. Dr. Kirkland believes that these drugs have the potential to revolutionize the field of geriatric medicine and provide treatments for diseases which have been hitherto untreatable. He also suggests that in addition to targeting senescent cells, aging research can benefit from targeting other fundamental processes of aging as all of the processes appear to be linked together. In doing this, he posits that researchers will be able to target multi-morbidity (presence of >2 concurrent diseases) in older adults.
Dr. Kirkland’s research has led him to subscribe to the unitary theory of fundamental aging processes, which suggests that the underlying drivers of aging are so interlinked that if we disturb one, we inevitably affect the others. Research based on this theory could be used to combine therapies that can simultaneously target multiple processes of aging. Dr. Kirkland uses the diabetes drug metformin as an example, as it’s been shown to inhibit senescent cells from making some of the factors that drive inflammation and age-related disease.
- Watch this Dr. Kirkland talk about current senolytics clinical trials
- Listen to this episode of the STEM-talk podcast to hear Dr. Kirkland discuss his most important findings and what he thinks of the future of senolytics
What news have you heard about senolytics? Would you eve try them? Share your thoughts with us: firstname.lastname@example.org
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