The Latest on Cellular Senescence in Type 2 Diabetes

One of the more unexpected recent findings relating to cellular senescence is that it appears to be an important part of the mechanisms that lead to loss of the pancreatic β-cells responsible for insulin secretion in both type 1 diabetes and type 2 diabetes - which are very different conditions, despite the shared name. The authors of the brief open access commentary noted here discuss the present state of this research.

Age is one of the major risk factors for the development of type 2 diabetes mellitus (T2D). However, the understanding of how cellular aging contributes to diabetes pathogenesis is incomplete and as a result, current therapies do not target this aspect of the disease. In recent work we showed that insulin resistance induced the expression of aging markers, suggesting that β-cell aging could accelerate the progression toward diabetes. Therefore, reversing the hallmarks of cellular aging presents a potential avenue for novel T2D therapies; in particular, transcriptomic analysis of aged β-cells pointed us toward cellular senescence as a promising target.

Senescent cells enter a state of long-term growth inhibition and replicative arrest after exposure to environmental insults, including genomic damage, oncogene activation, and reactive oxygen species. The resulting changes in gene expression impair cell function and proliferation while modifying intercellular signaling through the senescence-associated secretory phenotype (SASP). The potential paracrine effects of senescent β-cells highlight the importance of the β-cell SASP in driving metabolic dysfunction.

Along these lines, we demonstrated that senescent β-cells downregulated hallmark identity genes, upregulated disallowed genes, and secreted proinflammatory cytokines. We established two models of insulin resistance in mice: one using the delivery of the insulin receptor antagonist S961, and the other using a more physiologically representative high fat diet. In both cases, the metabolic stress increased the number of senescent β-cells while impairing glucose tolerance. Aging and SASP genes were also upregulated, but after insulin resistance was stopped, gene expression returned to healthy levels. This suggests that there might be critical windows during which β-cell senescence may be reversible. These results were consistent with experiments on human β-cells, in which senescence increased with age, body mass index, and in the presence of T2D.

Additionally, we found that the targeted deletion of senescent cells, or senolysis, in mice improved β-cell function, reduced blood glucose levels, and restored healthy expression levels of aging and SASP genes. Our findings highlight the transformative therapeutic potential of senolytic drugs in restoring β-cell function among T2D patients. The partial reversibility of β-cell senescence suggests that, consistent with recent publications, this is a non-binary phenomenon. External insults may create subpopulations of aged β-cells activating distinct levels of the senescence-associated regulatory progression.

The progression of damaged β-cells through this regulatory cascade likely accelerates T2D; eventually, the accumulation of senescent β-cells may cross a threshold inducing long-term metabolic dysfunction through the permanent loss of β-cell mass and function. The deletion of senescent β-cells or the reversal of senescence in a targeted subpopulation of aged β-cells may inhibit this cascade of dysfunction. To advance these therapeutic strategies, it is imperative to characterize the distinct subpopulations of senescent β-cells and the temporal expression patterns of senescence genes.

Link: https://doi.org/10.18632/aging.102502

Comments

@Reason, when do you think there will be cheap senolytics available in the market? Thanks

Posted by: Josep at December 5th, 2019 7:14 AM

@Josep: They are available now. There is no real barrier to obtaining dasatinib and quercetin, they cost little, and they have been shown to remove senescent cells in humans in much the same way as they do in mice.

Posted by: Reason at December 5th, 2019 7:52 AM

@Reason Do you take them? Do you recomend my parents, who are 67, to take them? Thanks

Posted by: Josep at December 5th, 2019 10:46 AM

@Josep: Read the literature on senolytics and make that decision for yourself. The only thing I recommend is that people should educate themselves on this topic and make informed choices.

Posted by: Reason at December 5th, 2019 10:56 AM

Ok Thanks!

Posted by: Josep at December 5th, 2019 10:57 AM

@Josep
Recommending a working treatment with quite nasty potential side effects would require 15 pages of legalese and disclaimers. And if the treatment is safe it is usually safe because it has only placebo effect.

for aged people there could be dangerous interference with the current medication. There cold be off Target toxicity, or even to strong reaction.

Posted by: Cuberat at December 5th, 2019 11:12 AM

It can be very daunting to know what to read, or where to start. You mention side effects? What are the side effects of the above mentioned combination? In what dose should we be taking them? I know these may be rookie questions. But I don't know where to look to find these answers. :(

Posted by: Ben at December 5th, 2019 3:02 PM

D&Q is much more than a placebo. Marked improvement in balance, power output, and post-workout fatigue. Balance improvement was totally unexpected and increased >700% time on a balance board with no training.

Posted by: Larry at December 5th, 2019 3:08 PM

Cuberat has a point about medication interference, something to consider. His point about a possible reaction is also important. Several educated biohackers that I've spoken with strongly suggest having someone with you - at the ready with an epi-pen if needed, for at least 2 hours after taking the D&Q. It's also recommended to have a barf bag as some people purge quite a bit after treatment. That said, it's very exciting that we have a cheap treatment NOW with tremendous potential. As for your 60 something year old parents, that's who this treatment is for!! Older people need it the most. If I were under 60 I'd wait for more studies, advancing technology....otherwise, times a waistin!

Posted by: August33 at December 5th, 2019 9:38 PM

and to make the things worse, the self-expermentaiton crowd has vary crappy objective measures of the effects of the treatment. The self reported mood change is the antithesis of objective, and even there the effects vary widely. Sometimes the senolytics will do almost nothing, in other case the changes are more pronounced . Without a good medical control and supervision all this is just a hearsay

Posted by: cuberat at December 6th, 2019 7:41 AM

@cuberat

Depending on your age you might run out of time.

I think bio hacking is still better than waiting for the magic pill.

Posted by: Stephan at December 6th, 2019 11:33 PM

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