Nature Medicine's December 2015 Focus on Aging Issue

The Nature Medicine journal's December 2015 issue is focused on aging and the present mainstream view of the road ahead towards treatments. Sadly, to my eyes at least, the mainstream view is still very much focused on investigating the mechanisms that cause variations between individuals in the outcomes and pace of aging - the scientific impulse towards generating full understanding at work. Genetics are at the forefront of this investigation, alongside prosaic environmental factors such as diet and lifestyle choices. This is, of course, absolutely the proven, correct path for the scientific method, and in the very long term all knowledge is useful. The mapping of the molecular biology of all observed states of human metabolism should continue, and in a better world it and all other scientific investigation would have a hundred times the funding it does at present.

To think this approach is the sum of the possible misses a very important aspect of our situation today, however. We stand at a point at which the research community might, given the right choices in funding research and development, bypass the need for the full understanding of the progression of aging and eliminate that progression by repairing its causes. The causes of aging are forms of cell and tissue damage that are comparatively well understood; there is consensus, good mapping of the basics of the biochemistry involved, little in the way of new additions to the list in the past twenty years, and where there is bickering, it is over which of these things is more or less important than the others, or over the big unexplored gulf of interlinked chains of cause and effect that lies between these well-understood causes and the complex mess they create given decades of aging. So we should skip the mess and fund the research to fix them all; the fastest and cheapest way to figure out relevance is to repair the damage in mice and see what happens. Well planned research programs and proposed treatments exist for all of these forms of damage, at varying stages of progress and funding, with the aim of producing novel forms of regenerative medicine capable of rejuvenation, turning back aging by removing its root causes.

There isn't yet much enthusiasm for this path from the mainstream. These researchers are focused on genetic variance, obesity, diet, calorie restriction mimetics, and a hundred other similar things that can swallow billions and decades to produce only knowledge and marginal gains in health and life span. It is a great pity, but at least there are some signs of progress towards better approaches. The Alzheimer's research community is working on clearance of amyloid, which is a form of repair technology that is much needed. Senescent cell clearance has gained more attention over the past few years after technology demonstrations proving the point that removal of these cells - which are themselves a form of damage when they gather in numbers - produces significant benefits when tried. Selling the damage repair approach as a coherent philosophy of action for the treatment of aging is still an uphill battle despite these gains. The zeitgeist of today is longevity-related genes and expensive programs proposing to use drugs to make the metabolisms of some people more like those of some other people who have a marginally greater - but still tiny - chance of living to extreme old age in a state of frailty. Seems a waste when we could spend the same resources to implement SENS rejuvenation treatments with a good expectation of the ability to turn back aging as a result.

Aging: toward avoiding the inevitable

Although many would say that aging is a normal part of human biology, age is also the greatest risk factor for a wide variety of chronic disease. Whereas the passing of time cannot be stopped, a growing body of research in model organisms suggests that it may be possible to delay the concurrent decline in health. Preclinical data support a 'unifying aging hypothesis,' that a common pathway or pathways regulate the aging process and its associated disease indications. Examples of these pathways are covered in the two reviews in this issue on senescence, and metabolism, and in a perspective on proteostasis. However, a recurring theme is the heterogeneity of human aging. As noted in a recent report from the World Health Organization, we do not all age at the same rate with the same prevalence of age-related diseases. Understanding the genetic and/or environmental factors accounting for this heterogeneity, faithfully modeling them in preclinical studies and controlling for them in clinical studies are perhaps the biggest challenges facing the field.

With regard to understanding the genetic underpinnings of aging, inbred model organisms will take us only so far. Interrogating the diversity of the human genome and correlating it with aging phenotypes will be essential. Thanks in part to ever-improving next-generation sequencing technology, these efforts are well under way. In 2007 the Scripps Translational Science Institute launched the Wellderly Study, starting by sequencing a panel of candidate genes associated with aging in cohorts of people and working towards whole-genome coverage. The Longevity Genes Project, which was initiated at Albert Einstein College of Medicine in 2008, also aims to find genes associated with longevity by using a cohort of centenarians, their offspring, and age-matched individuals unrelated to these offspring. More recently, Human Longevity, Inc., a company founded by J. Craig Venter, declared that it is "building the world's most comprehensive database on human genotypes and phenotypes to tackle the diseases associated with aging-related human biological decline." These data sets, which are increasing in terms of their numbers of patients and coverage of the genome, will be invaluable to researchers seeking to unravel the genetic factors that influence human aging.

In terms of clinical studies of therapies aimed at extending healthspan, there are several the challenges unique to this field. But all indications suggest that therapies will be coming. They may be established agents repurposed for treating aging, such as the rapamycin analogs used by Novartis in a proof-of concept trial to boost immune function in the elderly. They might also be new agents dedicated to 'drugging' aging. In addition to profiling the genomic and phenotypic aspects of human aging, Human Longevity, Inc. is developing cell therapies aimed at regenerating human tissues. Calico - a company launched by Google - has partnered with the Buck Institute for Research on Aging and the Broad Institute of Massachusetts Institute of Technology to identify therapeutic targets, and with AbbVie to develop drugs to hit these targets. Even with candidate drugs in hand, testing them in clinical trials will require innovation and collaboration with regulatory agencies. The Targeting Aging with Metformin (TAME) study is paving the way toward having healthspan recognized as an indication by regulatory bodies. The challenges ahead in dissecting the factors that contribute to aging and age-related disease loom large. With technology, collaboration and innovation, the aging research community will overcome them.

But not by using calorie restriction mimetics or by mapping and mimicking the differences between people slightly more likely to live to 100 and people slightly less likely to live to 100. Aging is caused by damage, and that root cause damage is the same in everyone. Repair the damage - in the same way in everyone, using mass-produced therapies - and you don't have to care in the slightest about understanding the vast complexity and genetic diversity inherent in the way in which a heavily damaged human biology fails in one way or another. Trying to nurse along a failing machine in its heavily damaged state with the hope that it will fall apart a little later than it would otherwise have done is a fool's game: expensive, hard, and with little to show for it at the end. The meaningful approach is to instead repair the machine, replace its parts, remove the rust and damage and dysfunction. That is the right path to extending or restoring a functional, healthy life span.

Comments

Yes repair seems logical and I think some of the SENS elements are coming along:

RepleniSENS: We are getting better at stem cell weekly on an almost weekly basis, not a month goes by I am not hearing something new and interesting about progress here. Stem cells were used to reverse dementia in a dog this week and my friend is also researching the very same thing on dogs so hopefully we will see the same results again speeding it into clinical testing on people.

OncoSENS: There are plenty of cancer solutions appearing with a range of promising approaches. Not my area tbh but there seems to be a lot of promising solutions in development.

ApoptoSENS: Senolytics MMTP wishes to test shortly in mice and prove it has health and lifespan benefits. We will be using Dasatinib & Quercetin as this appears to be the most effective compound so far in this class of drugs with a 30-40% clearance rate according to Scripps. We will test this and hopefully demonstrate removing SASP improves lifespan.

GlycoSENS: This should be a super high priority and I cannot believe more people are not realizing this. Glucosephane is a key to restoring stem cell signalling as it significantly increases TGF-β/pSmad3 signalling. We have seen what happens when these levels are reduced by the Conboy work. MMTP plans to test this in lifespan studies.

We hope this work may encourage focus on glucosephane if we can demonstrate the benefits of TGF-β/pSmad3 reduction using Alk 5 inhibition. If we had possible cleaving candidates to test we would but we hope Alk 5 encourages further work in the AGE breaker direction.

AmyloSENS: GAIM technology funded by MJ Fox seems very promising on that score and has improved since its original candidate drug in 2011 and now an improved version is even more effective at removing multiple amlyoids including amyloidosis.

LysoSENS: I would be very interested to hear about progress on this if any?

Posted by: Steve H at December 10th, 2015 6:55 AM

Unless there's some major SENS style regenerative breakthrough, I don't see the research community bypassing the need for a full understanding of the progression of aging anytime soon, sadly.

Posted by: Ham at December 10th, 2015 10:09 AM

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