Aneuploidy and Cellular Senescence in Aging

Aneuploidy is not very well studied in the context of aging, but at least a few research groups are looking into it. Aneuploidy describes the state of cellular dysfunction that arises from one or more missing or extra chromosomes, a problem that can occur as the result of malfunctions during cellular replication. Like all such issues in which an individual cell becomes damaged, the extent to which it causes downstream harm is largely governed by the degree to which a cell with aneuploidy can replicate, spreading its disordered state into a greater fraction of tissues. Alternatively, if aneuploidy occurs spontaneously with a great enough frequency, and also drives cells into senescence, then this might also be a path to significant harm in the course aging. Senescent cells contribute to aging via signaling, and even a comparatively small number of senescent cells can be very damaging.

This paper, I think, is an example of a fairly prevalent recent phenomenon: researchers retrofitting their current line of work on aging to more clearly build a link to cellular senescence. Cynically, I would say that this burst of rethinking is driven by the sizable influx of funding into the research and development of means to destroy or reprogram senescent cells. Now that it is broadly acknowledged that cellular senescence is a contributing cause of aging, there is funding for related projects, and the activities of researchers tend to be steered by the availability of funds.

Aging is characterized by a progressive loss of physiological integrity and function over time. Being the largest risk factor for the incidence of cancer, cardiovascular, and neurological diseases, it results from several interconnected molecular processes that decline with advancing age and that are commonly categorized in nine "aging hallmarks". Among these hallmarks, which are nevertheless interdependent, epigenetic alterations and cellular senescence have gained increased relevance, as they have been modulated by the current mainstream anti-aging therapies.

Although a single universal marker for cellular senescence is still to be unveiled, senescent cells present several distinguishing features in vitro, such as flattened morphology and enlarged nuclear size, and increased senescence-associated β-galactosidase (SA-β-Gal) activity. Moreover, cellular senescence is accompanied by the development of a senescence-associated secretory phenotype (SASP), a distinctive cell-specific secretome. There has been intensive research examining the regulatory mechanisms behind cellular senescence and SASP. It is now clear that this occurs on two fronts; while p53 and pRB are responsible for halting cell cycle progression during cell senescence, the regulation of the secretory component seems to be mainly mediated by the NF-κB signaling pathway.

For several decades, many observations have demonstrated an incidence of aneuploidy along human chronological aging. Aneuploidy is defined as an abnormal chromosome number resultant from chromosome mis-segregation during cell division, in both gametes and somatic cells. The molecular mechanisms behind the age-associated aneuploidy globally point to alterations in the expression levels of genes that are involved in the cell cycle and in the mitotic apparatus. Interestingly, genomic instability, telomere erosion, epigenetic drift, and defective proteostasis, which are the primary hallmarks of aging acting as initiating triggers leading to secondary hallmarks, have all been reported to induce mitotic defects and aneuploidization. Moreover, aneuploidy resulting from lagging chromosomes/weakened mitotic checkpoint has been associated with cellular senescence and premature aging.

While we are left to learn more what a truly senescent cell is, if there is the need of long- or short-term clearance from the organism, and, more importantly, if we can rescue the still proliferative "pre-senescent" cells. In this context, a new candidate hallmark for aging arises, aneuploidy, an abnormal chromosomal number that results from mis-segregation events during mitosis, which has been linked to normative aging and age-associated diseases, with the underlying mechanisms being poorly understood. Recently, aneuploidy was shown to increase with advancing age due to an overall dysfunction of the mitotic machinery. Furthermore, several reports have uncovered the impact of aneuploidy on cellular fitness and proliferative capacity, with several characteristics of aneuploid cells overlapping with those that are found in aged cells.

Our latest work provided insight as to how senescent cells arise, by demonstrating that elderly proliferative cells, primed with the expression of a senescence core gene signature, evolved into permanent cell cycle arrest (full senescence) following passage through a faulty mitosis. This further supports that improving mitotic fitness may be used as a potential anti-aging strategy, thereby counteracting the SASP-induced inflammatory microenvironment and helping to protect stem cell and parenchymal cell functions.

Link: https://doi.org/10.3390/ijms20040938

Comments

This isn't relevant to the article but I wanted to commend you for your dedication to this site.

I was wondering since you've started this website in 2002 how much closer have we've gotten to the start of these therapies?

A overly enthusastic man on Quora suggests 10-20 years, and I was wondering if that's seen as a outrageous fast time compared to other people who are informed, espically you.

Posted by: Khand at March 1st, 2019 7:05 AM

@Khand

I do agree. Most of the blogs have a precious few good articles. And the rest is the kind of 20 foods doctors hate and such.

Reason is doing a really good job of covering the state of affairs. This site is a meta-analysis of its own...

As for when we can expect the first therpies, it depends how you define it. Metformin is ab week CR mimetic and is available. So are fisetin, quercetin and calorie restriction)/fasting. Those are not publicly accepted and we don't know what is the best protocol. So I would call those generation 0. Stuff that is a bit better than placebo but not by much.

In the next 10 years we will see some generation 1 treatments. Probably even in the next 3-4 years. I hope they will arrive soon enough for my parents...

Posted by: Cuberat at March 1st, 2019 7:47 AM

My current fear is cancer and organ failure as well as amyloidosis, those are scourge standing in our way.

Posted by: Dokuganryu at March 1st, 2019 10:48 AM

I think the recent comment by Abrey De Grey is very interesting:
He sees a 50 % chance that mice can live to 5 years, in 3 years time. And this with therapies given when the mice is 2 years old. Today, mice don't live longer than 3 years.
When this happens, it will be obvious that we can do something similar with humans, and money will be pouring in.

Posted by: Martin Andersen at March 1st, 2019 1:13 PM

@Mark Borbely,

Thanks for the link for Mellons presentation.

I am hopefully there will be a huge paradigm in health care by 2030 (it certainly looks like it with his comments along with Audrey and all the other biotech in the headlines) that we can easily take some treatment that can give us an extra 10 years of life without paying an arm and leg for it. There are many technologies on line now and changing of mindset for the rich and venture capitalist that I think it will be very different from the current environment.

Posted by: Robert at March 1st, 2019 1:29 PM

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