Another Set of Popular Science Articles on the Prospects for Aging Research

Science News recently lumped together a few popular science articles on aging research into a special issue on the subject. As the blurb notes, aging is very much neglected in comparison to its importance, and accepted despite the damage it does. Defeating aging should be the primary focus of medical research, given that it kills about twice as many people as all of the other causes of death put together, and is the root cause of an even larger proportion of disability, pain, suffering, and medical expense. That it isn't is just another sign that we humans are not good at priorities and common sense.

Everyone ages. Growing old is a fundamental feature of human existence. But, our scientific understanding of aging pales in comparison to its significance in our lives. While new studies reveal exciting prospects for slowing the effects of aging, its causes and extensive effects remain enigmatic. Scientists are still divided on some fundamentals of aging, and that's why aging research raises some interesting questions. For example, how does it change the brain? How did different life histories evolve? How old is the oldest blue whale? This special report addresses those questions and more.

I'll link to the first of the articles below, and leave an exploration of the others as an exercise for the reader. That first article is a fairly standard example of this sort of thing, covering a few recent and more publicly discussed research initiatives in the field. As is usually the case, it largely focuses on ways to modestly slow aging, such as calorie restriction mimetic research, or to spur greater stem cell activity in old individuals, such as some of the leads resulting from parabiosis research. It omits any explicit mention of the SENS approach to rejuvenation research, which is, sadly, still par for the course, even as it examines some of the current progress in senescent cell clearance, a topic that has been on the SENS list for fifteen years at this point. That was a decade in advance of any meaningful attempts to remove senescent cells in the laboratory, and it is worth recalling that, as for other aspects of SENS, this was mocked within the scientific community at the time. Those who said as much back then now largely pretend that they agreed this was a viable approach all along; such is human nature. The SENS vision for medical control of aging hasn't changed, and is well known in the field now, but still working its way to greater material support. So when a journalist calls up half a dozen researchers to chat about their research the odds are still pretty good that none of those worthies will have any aspect of the presently active SENS programs in his or her list of pet topics.

This is unfortunate, as it means that most popular science journalism continues to propagate an unrealistic view of the near future of aging research, especially when it comes to expectations for the odds of greatly extending the healthy human life span. There is an opportunity to be seized here, a way to build rejuvenation therapies that can extend life to a far greater extent than is possible via approaches such as calorie restriction mimetics, trials of drugs like metformin, or other marginal strategies that aim to alter the operation of metabolism so as to slightly slow aging. Putting SENS repair strategies like senescent cell clearance side by side with calorie restriction mimetics is to create a false equivalence - these things are not the same at all. Repair can in principle create rejuvenation and indefinite healthy life spans, only limited by the quality of the repair implementation. All of these other technologies to slightly slow aging can do no such thing: they are very limited in comparison, and even if perfected can at most add a few years to human life spans. There is a huge difference between repairing the damage that causes aging and merely slowing down the accumulation of that damage, and that difference is being ignored by people who should know better. Why does this matter? Because building the rejuvenation therapies envisaged in great detail in the SENS proposals, some of which are coming into being in a few startup companies at the present time, requires large-scale support: money, advocacy, discussion, and most importantly widespread understanding.

A healthy old age may trump immortality

On the inevitability scale, death and taxes are at the top. Aging is close behind. It's unlikely that scientists will ever find a way to avoid death. And taxes are completely out of their hands. But aging, recent research suggests, is a problem that science just might be able to fix. As biological scientists see it, aging isn't just accumulating more candles on your birthday cake. It's the gradual deterioration of proteins and cells over time until they no longer function and can't replenish themselves. In humans, aging manifests itself outwardly as gray hair, wrinkles and frail, stooped bodies. Inside, the breakdown can lead to diabetes, heart disease, cancer, Alzheimer's disease and a host of other problems.

Scientists have long passionately debated why cells don't stay vigorous forever. Research in mice, fruit flies, worms and other lab organisms has turned up many potential causes of aging. Some experts blame aging on the corrosive capability of chemically reactive oxygen molecules or "oxidants" churned out by mitochondria inside cells. DNA damage, including the shortening of chromosome endcaps (called telomeres) is also a prime suspect. Chronic, low-grade inflammation, which tends to get worse the older people get, wreaks so much havoc on tissues that some researchers believe it is aging's prime cause, referring to aging as "inflammaging." All these things and more have been proposed to be at the root of aging.

Some researchers, like UCLA's Steve Horvath, view aging as a biological program written on our DNA. He has seen evidence of a biological clock that marks milestones along life's path. Some people reach those milestones more quickly than others, making them older biologically than the calendar suggests. Others take a more leisurely stroll, becoming biological youngsters compared with their chronological ages. Many others, including Richard Miller, a geroscientist at the University of Michigan, deny that aging is programmed. Granted, a biological clock may measure the days of our lives, but it's not a ticking time bomb set to go off on a particular date. After all, humans aren't like salmon, which spawn, age and die on a schedule. Instead, aging is a "by-product of running the engine of life," says biodemographer Jay Olshansky of the University of Illinois at Chicago. Eventually bodies just wear out. That breakdown may be predictable, but it's not premeditated.

Despite all the disputes about what aging is or isn't, scientists have reached one radical consensus: You can do something about it. Aging can be slowed (maybe even stopped or reversed). But exactly how to accomplish such a counterattack is itself hotly debated. Biotechnology and drug companies are developing several different potential remedies. Academic scientists are investigating many antiaging strategies in animal experiments. (Most of the research is still being done on mice and other organisms because human tests will take decades to complete). Even researchers who think they have finally come up with real antiaging elixirs say they don't have the recipe for immortality, though. Life span and health span, new research suggests, are two entirely separate things. Most researchers who work on aging aren't bothered by that revelation. Their goal is not necessarily extending life span, but prolonging health span - the length of time people live without frailty and major diseases.

The glass half full view, to counter my glass half empty points above, is that one of the SENS approaches to treating the causes of aging has finally taken wing and left the nest in these past few years. Senescent cell clearance now appears in popular science articles, is worked on by a number of unaffiliated research groups, has demonstrated life extension in mice, and is under clinical development in multiple companies. As removal of senescent cells proves its worth, other lines of SENS research, other forms of damage to be repaired to create rejuvenation, and the overall strategic approach of focusing on damage and its repair, will gain greater support.

Comments

Somatic cell reprogramming of aged cells can be associated with rejuvenation, erasing certain age-associated features, and illustrating the reversibility potential of aging. Nishino & Umezawa have established a large number of hiPSCs derived from various human tissues and have obtained their DNA methylation profiles. Comparison analyses indicated that the epigenetic patterns of various hiPSCs, irrespective of their source tissue, were very similar to one another and were similar to those of human embryonic stem cells (hESCs) See http://link.springer.com/article/10.1007/s13577-016-0139-5
Epigenetic marks such as the acetylation of histones & DNA methylation change substantially when animals age. Nevertheless epigenome editing by a CRISPR-Cas9-based acetyltransferase (http://www.nature.com/nbt/journal/v33/n5/full/nbt.3199.html) &/or CRISPR-based approach for targeted DNA demethylation (http://www.nature.com/articles/celldisc20169) activates genes from promoters and enhancers. Moreover, we can now selectively enforce silence to the elected genes by using reprogrammable CRISPR/Cas9-based system for inducing site-specific DNA methylation. Why not to try to turn the old mouse into the young one by using these tools? To recreate in the cells of old mice the profile of active genes, DNA methylation and histone marks H3K9me3 like in young. Of course there are obstacles in the form of the Extra-Cellular Matrix full of glucosepane. But the main thing is to start, and the solutions will come. If even a non-specific action on DNA methylation (experiments with 5-azacytidine http://www.pnas.org/content/113/16/E2306.abstract ) allows to reprogram the cells, why not to try the selective one?

Posted by: Dmitry Dzhagarov at July 23rd, 2016 12:47 AM

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