More Data on the Tissue Specificity of Senescent Cell Accumulation with Age in Mice
As work progresses on the clinical development of senolytic therapies to selectively destroy harmful senescent cells in old tissues, it is becoming ever more necessary to have a better understanding of just how many senescent cells are present in any given tissue with age. Not all tissues acquire lingering populations of these cells at the same pace. Further, most current senolytic therapies are quite tissue specific, either because of the biodistribution characteristics of the drug, or because effectiveness varies in destroying senescent cells of different cell types.
Prioritization of development efforts requires some idea as to which tissues are more burdened by senescent cells, and thus more subject to the senescence-associated secretory phenotype in producing dysfunction and age-related disease, at least in the small molecule portion of the field. It is possible that Oisin Biotechnologies at least could just power through this challenge by saturating all tissues in the body with their non-toxic, highly selective suicide gene therapy vector. Brute force is sometimes an option.
Non-invasive ways of quantitatively assessing the presence of senescent cells in different tissues are also much needed, because we'd all like some idea as to how effective a given therapy might be. The dasatinib and quercetin senolytic combination is readily available, and you'll bump into people who have used it at longevity industry conferences, but few of those have undergone the biopsies that are presently the only viable way to make before and after comparisons of senescent cell burden. Better methods are on the horizon, such as the circulating microRNA approach under development at TAmiRNA, but they are not on the market yet. These tools will be needed to enable a more rational design of the next generation of senolytics, and they would certainly help in the clinical development of the present generation of senolytics.
Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice
In this study, we provide a comprehensive measure of senescence in aged wild type (WT) mice. Senescence was quantified in multiple tissues, using numerous methods and numerous molecular endpoints, and we compared measures with that of young adult WT mice. We used this as a benchmark to determine whether Ercc1-/∆ mice, that exhibit accelerated aging, accumulate senescent cells in physiologically relevant tissues.
As measured by qRT-PCR and p16LUC signal, levels of p16Ink4a were significantly increased in aged WT mice compared with younger adult mice, as expected, p16Ink4a and p21Cip1 expression are found in peripheral T cells and numerous tissues (10 of 14 total tested) with the exception of heart and skeletal muscles. The differences in senescent cell burden in tissues could be reflective of different levels of genotoxic stress and/or different responses to that stress (e.g., selection of cell fate decisions: senescence or apoptosis). Near complete concordance was found between the expression of senescence markers in aged WT (2.5 years) and progeroid Ercc1-/∆ (4-5 month) mice, in terms of tissue specificity and expression levels.
The systemic burden of senescent cells was equivalent at the halfway point of lifespan in each of Ercc1-/∆ and WT mice, although the strains have vastly different lifespans. This supports the notion that senescent cell burden correlates with organismal health and may prove to be useful in predicting health span, or the remaining fraction of life that is disease-free. The data also support the conclusion that Ercc1-/∆ mice spontaneously develop senescent cells in the same tissues and at similar levels as WT mice, albeit more rapidly, supporting the notion that these animals represent a model of accelerated aging.
@Reason
You mentioned OISIN, however there were no news from then for quite a long time. Do you think there will be some news soon-ish?
This study shows that a progeroid mouse and a wild type mouse have the same senescent cell burden in the same tissues, which they take to imply that senescent cell burden is highly indicative of remaining health span (reasonable enough, especially given other recent research on senescence). And I remember that the old mayo clinic experiment of total removal of senescent cells from mice via gene therapy resulted in mice that seemed to acquire no phenotypic traits of aging, like at all. Yet maximum lifespan was not extended, nor has maximum lifespan been extended in follow-up experiments.
Ok, so my question: has anyone tried to figure out what is killing mice which have had robust senescent cell clearance? Do these mice quickly acquire phenotypic traits of aging right at the ends of their lives, or are they dying from some aging process unrelated to more general organism aging (e.g. accumulated proteins causing heart dysfunction or similar)?
*same senescent cell burden halfway through their respective expected lifespans
@Gheme
Here is one article about that study:
https://www.nih.gov/news-events/nih-research-matters/senescent-cells-tied-health-longevity-mice
Quote
...treating mice to remove senescent cells extended their median lifespans by 17% to 42%, depending on sex, diet, and genetic background. The treated mice typically had a healthier appearance ...
The mice still aged albeit a bit slower and some of the diseases were less common or severe.
Mind that there might many different dysfunctional and harmful cells, even if they are not explicitly senescent in the sense of having p16 pathway. There are also as other root causes of aging( SENS lists 7 groups), so even if every single cell in the body was not aging the body as a whole will. Also the genetic intervention in that study most probably was quite a crude tool.
But even if the maximum lifespan is not increased, the median and healt h hspans will. That alone would be a huge win. And for the first iteration we need a safe and efficient protocol of applying Dasatinb+Quercetin and Fisetin. That requires human safety and efficiency studies. That takes time and money... I am a bit disappointed that we don't have such studies running right now on large scale. Self experimentation is nice and trendy but doesn't quite cut the mustard ...
And a bit off topic. A new research finds that man have more and earlier age declined in immune system.
https://www.nature.com/articles/s41467-020-14396-9
@Cuberat: There are plenty of Oisin and OncoSenX scientific results to report but it is mostly all embargoed while undergoing peer review. May be many months before it gets released.
"Prioritization of development efforts requires some idea as to which tissues are more burdened by senescent cells, and thus more subject to the senescence-associated secretory phenotype in producing dysfunction and age-related disease, at least in the small molecule portion of the field. It is possible that Oisin Biotechnologies at least could just power through this challenge by saturating all tissues in the body with their non-toxic, highly selective suicide gene therapy vector. Brute force is sometimes an option. "
Given that Oisin's lipid nanoparticles didn't outperform dasatnib + quercetin in mouse lifespan troubles, it does not seem that Oisin's lipid nanoparticles have a distribution advantage, in mice at least.
Or they do have a distribution advantage, but this does not lead to longer lifespans in mice but might in humans.
in these papers the vocabulary is:
maximum lifespan = maximum lifespan ever achieved in the history of science for a single individual of this species
median lifespan - maximum lifespan of an individual in the study
@jimofoz: "Given that Oisin's lipid nanoparticles didn't outperform dasatnib + quercetin in mouse lifespan [studies], it does not seem that Oisin's lipid nanoparticles have a distribution advantage, in mice at least."
I've not seen mouse D+Q lifespan studies; can you provide a link?
@Gary - always good to see you in the comments.
i might be misremembering about D+Q lifespan studies in mice. It would be interesting if someone would carry them out though.
@jimofoz: This paper by Kirkland (Fig 6) does have a lifespan report on D+Q treatment of aged mice - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082705/
@Gary: do you have any estimate of how long it will take for oisin therapy to be available to the public? 2, 5 or 10 years ballparks?
I would guess that there are many more therapies envisioned , which wait for funding and human trials. Let's hope all works well.
@Algalon: It's unwise to speculate about timescales since everything is dependent upon factors largely out of our control, like money and regulatory risk. The typical answer is 5-10 years but we've been at this for five already!
In answer to Gheme's question, and to the discussion of senescence in general - people are too focused on the binary senescent or non senescent perspective. In biology, cells will all range on some scale of relative senescence. Removing the worst ones will help health, but there will always be more forming, at ever greater rates with age - hence the squaring of the curve.
@Mark
Dont forget about the Pareto principle that a
small fraction of SnC can cause the most of the damage/pro inflammatory cytokins. Most likely there is a power wall distribution (similar to wealth, planet size, etc) that would probably mean 1 percent of SnC are causing 50 % of the damage, 20 % -80, etc. So, if you can get rid of the worst offenders, even a few percent, the benefits would be already huge. All subject to verification, of course...
@Gary: Thanks for the answer. What about just the technology development though? Would it be ready for humans this year given no regulations/clinical trials and whatever money?
@Cuberat - maybe,it depends on the distribution of the senescent phenotype, i.e. a few very senescent and lots of functional cells, or many cells of an intermittent phenotype, for example. The mouse results so far indicate definite benefits but also diminishing returns from repeated senolytics. Not a bad result - extended healthspan, but not much movement in lifespan - to go further we will need more than a senolytic monotherapy.
@Cuberat
I was thinking of the way-old 2011 paper from Nature ('Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders') which says: "In tissues-such as adipose tissue, skeletal muscle and eye-in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes." But actually that's in progeroid mice, so thanks for the update.