Targeting Cellular Senescence as an Intervention in Aging

Senolytic drugs that destroy senescent cells, and later on, other senotherapies that either prevent senescence or block the senescence-associated secretory phenotype (SASP), are going to be very important in the treatment of aging. Senescent cells accumulate with age and are highly damaging to tissues. Via the SASP, even comparatively small numbers of lingering senescent cells actively disrupt health and tissue function, driving age-related disease and mortality. Removing these errant cells causes quite rapid rejuvenation in animal studies, meaningfully reversing the progression of numerous age-related conditions. Other approaches to the treatment of aging attempted to date have so far failed to produce results that are as robust and impressive as the data emerging from the study of senolytics. Within a few years we'll know just how well that translates to humans for at least a few conditions, as a number of clinical trials are presently underway or planned.

Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin. In preclinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multimorbidity, and accelerated aging phenotypes. In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae. Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells. We hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine.

Multiple interventions that target primary aging processes are currently being explored. Senescent cell burden represents one fundamental aging process that has been carefully studied. Targeting it at the preclinical level by genetic and pharmacologic reduction has yielded compelling findings that support the geroscience hypothesis. Translation of promising pharmacologic interventions in the form of senotherapeutic agents has begun to assess safety and target engagement.

Reduction in senescent cell burden could be transformative to clinical practice, especially geriatric medicine. Clinically relevant primary endpoints for older adults will likely include aspects of both objective and subjective physical functioning, since these are predictive of morbidity and mortality, contribute to risks of cognitive decline and injury, are prominent components of geriatric syndromes, and are consistent with measurable improvements being made in the short term. Biomarker discovery will be facilitated by larger clinical trials, measurement of changes in multiple analytes in multiple target specimens, and replication of biomarker feasibility and utility across multiple sites within a single study and among different studies. In the longer term, it should be possible to assess the delays in onset of chronic diseases and geriatric syndromes with compression of morbidity, using interventions based on reduction of senescent cell burden and other interventions in the aging process.

Link: https://doi.org/10.1016/j.molmed.2020.03.005

Comments

Hi Reason, I was wondering your take on the latest news from Ponce de Leon Health, as it relates to addressing the issues caused by senescent cells? From their site, it seems they have a method of "blocking inflammatory cytokines of senescent cells", which is seemingly non-invasive, low-cost, and low-risk to the consumer...albeit possibly "targeting the symptoms", perhaps, more than focusing farther up the chain (like senoyltics would function).

thank you for your terrific contributions,
Eugene

https://www.lifespan.io/news/pilot-study-results-suggest-epigenetic-age-reversal/

Posted by: Eugene at July 1st, 2020 12:18 PM

@Eugene, Reason and everybody
"The company claims that it has been successful in reducing the epigenetic age of participants by an average of 8.5 years with its dietary supplement Rejuvant...."

By 8.5 years !!!??? Don't you think that it looks to be too good to be true?

Posted by: Alek Ales at July 1st, 2020 5:47 PM

@Alek Ales
Epigenetic and methylation clocks so far are quite unreliable. Almost garbage. We don't even understand what the measured value actually means. On top of that a lot of readings can be influenced by some short term changes and the protocols are not the same for different studies. For example, one of the visual clues for older age we have is grey hear. Let's do a thought experiment. If we had a treatment that selectively destroyed or suppressed the hair follicles with only grey/white hair this "clock" would show rejuvenation and even improved quality of life for people with enough hair that is still not grey.

Most of the epigenetic clocks are even worse.

Posted by: Cuberat at July 1st, 2020 9:49 PM

It did all seem to come down to the quality of the biomarker/measurement/clock (well, on top of the claim itself)...on their site they seem to say the 'margin of error' is not large. However, this compound seems to do several great things, so, I hope they use maybe a Horvath clock or something more "respectable" (?) in the field, to tout their results. I think it would be a huge win if they had something which didn't need FDA approval, and was able to reverse aging even just a few years, to be honest. I wonder why they would even use the clock they did, if in fact it could be classified as "almost garbage"... ?

https://trumelabs.com/our-science/

Eugene

Posted by: Eugene at July 2nd, 2020 1:45 PM

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