The Present Standard Cancer Therapies Increase Biological Age

The current standard treatments for cancer, chemotherapy and radiotherapy, are quite unpleasant and harmful; no-one would voluntarily undergo them given a better alternative. In fact, treatment makes people physically older, accelerating the processes of aging. There is evidence to suggest that this is due to an added burden of senescent cells. Cells become senescent in response to damage or a toxic environment, and there is plenty of that going around in any earnest attempt to treat cancer with radiation or chemical agents; in fact, many cancer therapies are intended to aggressively induce senescence in tumor cells.

The presence of senescent cells is one of the causes of aging. These cells remove themselves from the usual cycle of replication, and in normal circumstances near all self-destruct or are destroyed by the immune system. Unfortunately, enough linger to contribute to aging. They produce harm through inflammatory signaling, the senescence-associated secretory phenotype (SASP), that corrodes tissue structure and disrupts tissue function - insignificant in small amounts, but very damaging given a sizable number of such cells. There are no doubt other mechanisms by which present cancer therapies touch on the causes of aging, however; given that aging is damage, and cancer treatments are damaging in many ways, we should probably not be surprised to find that aging is accelerated.

Studies among long-term cancer survivors indicate numerous possible clinical complications resulting in considerable morbidity and mortality, related to chemotherapy, radiation therapy, or both. A wealth of observational data on the development of late complications in cancer survivors are available, but information documenting the pathological basis for development of these effects is sparse. To understand the biology of late effects better and provide a foundation for the development of interventions, it is important to characterise late effects at the cellular level. Cancer survivors, in general, appear to develop age-related diseases and phenotypes sooner than members of the general population. This is likely because damage to normal tissues from cancer therapies diminishes physiological reserve, accelerates processes typically associated with ageing, or both.

The roles of telomeres, senescent cells, epigenetic modifications, and microRNA have been described in terms of their contributions to the pathobiology of accelerated ageing. However, published data linking clinical phenotypes seen in cancer survivors with processes of accelerated ageing at the cellular level is lacking. On a microscopic level, ageing is a consequence of gradual, lifelong accumulation of molecular and cellular damage and loss of physiological integrity. Hallmarks of ageing include genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, chronic low-grade inflammation, and cellular senescence. We have demonstrated with clinical data that cancer survivors develop the health-related manifestations of ageing more quickly than their peers. While ageing prematurely is a better alternative to dying prematurely, a better understanding of what drives this process presents an opportunity for improvement.

As many cancer treatments appear to induce an accelerated ageing-like state, interventions that target fundamental ageing processes may have a role in cancer survivors. Since many cancer therapies induce cellular senescence, among the most promising agents are senolytics, drugs that selectively eliminate senescent cells and SASP inhibitors, which blunt local and systemic effects of the SASP. These agents alleviate frailty, restore progenitor function, reduce insulin resistance, rescue cardiac and vascular dysfunction, decrease adverse effects of radiotherapy and reduce osteoporosis in a variety of animal models of ageing and disease. Senolytics are effective when administered intermittently, potentially reducing toxicity, and resistance to these drugs is unlikely to develop as, unlike cancer cells or microbes, senescent cells do not divide.

Link: https://doi.org/10.1136/esmoopen-2017-000250

Comments

OT: Congratulations for reaching this year's SENS patrons goal!

Posted by: Antonio at December 20th, 2017 9:39 AM

Congrats.

Posted by: Anonymoose at December 20th, 2017 11:15 AM

Valter Longo has done work on better toleration of chemo after being on a fast-mimicking diet. His theory on why this is effective, as stated in his interview with Rhonda Patrick, is that it sets up survival of normal cells while priming cancer cells for apoptosis.

Posted by: MikeM at December 20th, 2017 11:51 AM

At the same time SENS cannot prove WILT which can end cancer forever because of lack of funds:

It's been slow but steady. On the telomere control side, other groups have made nice progress in inhibiting telomerase-mediated elongation (see especially Jerry Shay's 2015 paper on 6-thio-2′-deoxyguanosine) and we have developed a much faster and cheaper assay for ALT that will facilitate the discovery of anti-ALT drugs. On the stem cell replacement side, we funded a study to look for the ability of early-generation telomerase-knockout haematopoietic stem cells to rescue longevity in late-generation telomerase knockout mice, and it worked (it was tricky because we needed to rescue their gut problems with another mutation) but we could only afford to do a small study so we barely made it to statistical significance and we haven't published it. Our parallel work on the gut, led by Graca Almeida-Porada at Wake Forest, made modest progress but unfortunately we have had to suspend that project because of lack of funds.

I remain hopeful that we can get WILT to work - but I also remain hopeful that we won't need to, because simpler therapies will work well enough. In particular, the progress in cancer immunotherapy over recent years has been dramatic, and it might just be enough to make WILT unnecessary. We won't stop working on WILT until we're sure that that is the case, though!

https://www.quora.com/Whats-been-the-progress-if-any-on-the-WILT-Whole-body-interdiction-of-the-lengthening-of-telomeres-strategy

Posted by: Ariel at December 20th, 2017 3:24 PM

Aubrey always strikes me as being extraordinarily open minded, for example here he is open to not needing WILT. I asked him about epigenetic reprogramming once, expecting the kind of put down I'd most likely get from commentators here - but he was optimistic about its prospects. SENS is valuable because it's addressing all the root causes of aging, but we won't necessarily have to implement it as Aubrey originally envisaged.

Posted by: Mark at December 21st, 2017 9:16 AM

@Mark, I am not so open minded as Aubrey and would prefer full WILT and know that I can forget about the problem instead of being regularly checked for cancer and being cured even if it would be as curable as flu. As far as you know even being easily curable flu, hovewer, kills many people each year. I will prefer reseed my stem cells each year.

Posted by: Ariel at December 21st, 2017 10:25 AM

@Mark, 'Aubrey always strikes me as being extraordinarily open minded', -- because he is an engineer who wish to solve the problem, not to produce another one 'universal' theory! ;-)

Posted by: Ariel at December 21st, 2017 11:24 AM

Today I was viewing some new Aubrey interviews/debates on Youtube. I noted that when he is asked what he thinks about other people pursuing different approaches than SENS, he says he is totally in favour of it, because he can be wrong about SENS or it could take longer than he thinks, etc. but when he is asked about specific examples he is not so gentle. For example:

- Calico: It's a huge waste of money and Larry and Sergey should know better, because they already educated themselves about gerontology (including SENS) 15 years ago.

- Personalized medicine for cancer: It's a stepping stone until we have WILT, which will probably take longer to develop. PM is a way to improve a form of medicine that barely works (modern oncology) and it will fade away when we have SENS 1.0.

- Ambrosia: It's highly unlikely that it will work. To begin with, because it's not real parabiosis, only transfusions (i.e., they don't extract the old blood, only inject young blood, so the amount injected must be very tiny).

- Nanotechnology: Probably wet rejuvenation biotechnology will arrive sooner and make nanomedicine unnecessary. Only if the former encounters an unexpected obstacle can the latter be useful, probably.

- Research on naked mole rats: it can be useful for finding new methods to fight cancer.

Etc.

Posted by: Antonio at December 21st, 2017 12:01 PM

@Ariel, I suspect there will always be some balance to be struck between aging and cancer, and if we go down the WILT route we must be mindful we would then age much faster without regular stem cell infusions. And I also suspect such infusions will be very tricky, given the number of different stem cell niches and the problems currently being encountered with actually getting infused stem cells to do what they are supposed to. No doubt Aubrey will know all about this problem and how it is being tackled in his job at AgeX, but he probably also has one eye on the work of Vera Gorbunova and others as a in vivo alternative.

Posted by: Mark at December 23rd, 2017 11:41 AM

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