Fight Aging!

The difference between having and not having an accurate, rapid, low-cost measure of biological age is night and day. If such a thing did exist, then it is immediately the case that a good few dozen interventions could be rapidly tested in humans, taking a month or two between before and after measurements. The cost is low enough that volunteer groups and philanthropy could manage it. Look at what Betterhumans is doing in trials of cheap senolytic compounds, for example, and then add a robust assessment to that in order to definitively say whether or not rejuvenation occurred. I expect that only a few of the obvious candidate interventions that people will put forward will in fact turn out to make a difference. This is still important: the absence of results for the rest should go some way towards shutting off useless work on supplements and dietary tinkering that absorbs a great deal of time and funding both within and without scientific community.

Is there such a thing as an accurate, low-cost test that measures biological age, however? The later variants of the epigenetic clock might fit the bill, though it is still impossible to say whether or not they broadly reflect the causes of aging, or are tied to just a few narrow causes of aging. Absent a way to effectively reverse one of those narrow causes on its own, the mystery will likely persist; as of today, only senolytic therapies are capable of that feat, and they are not yet widely tested in humans. That the clock is uncertain in its mechanism of action is actually all the more reason to be running these studies. Both the clock and interventions alleged to slow or reverse or compensate for the progression of degenerative aging can be validated against one another.

The posts noted here cover an outline of one possible direction for evaluation of interventions against the epigenetic clock. They are largely not the sort of thing I believe should be the primary focus of the research community. These approaches are for the most part calorie restriction mimetic and similar compounds that trigger or enhance stress responses. All such methods have been shown to scale down in the extension of healthy life span as species life span increases. Calorie restriction itself produces 40% gains in mouse life span, but is unlikely to change human lifespan by more than five years or so. That said, there is merit, I think, in being able to show, robustly, that these approaches have only small effects, and thus redirect research and development efforts elsewhere, hopefully towards the SENS damage repair approaches that can in principle produce rejuvenation rather than just a slight slowing of aging.

The Mother of All Clinical Trials, Part I

There are a great number of promising interventions that might have anti-aging benefits. There is a testing bottleneck, which means that we don't know what works. By way of contrast, there is a well-documented catalog of life extension interventions in lab worms, but for humans we're mostly in the dark. To complicate things further, lab worms are clonal populations, while every human is different, and there are growing indications that many if not most medications work for some people and not others. Horvath's methylation clock is a disruptive technology that could make human testing of longevity interventions ten times faster and 100 times cheaper than it has been in the past. No one is yet doing this kind of testing, but you and I should be advocating vigorously, and volunteering as subjects to help test whatever it is that we are already doing.

There are a great number of promising interventions that might have anti-aging benefits, singly and in combination. Some are already approved and safe for use in humans, yet we don't know what will be most effective. Because human longevity studies are prohibitively slow and expensive, none have ever been funded or conducted. (We know only accidentally that aspirin and metformin lower mortality rates in humans, because these drugs were prescribed to tens of millions of people beginning in the 1960s for cardiovascular disease and diabetes, respectively, with no premonition that they might extend lifespan.)

Testing of anti-aging interventions in humans has been so expensive and slow that we have been forced to make inferences from animal tests, supplemented by historic (human) data from drugs that happen to have a large user base going back decades. As it turns out, it is much easier to extend lifespan in worms than in mammals, and even the interventions that work in rodents don't always work in humans. Conversely, there are drugs that work in humans that don't work in mice - how are we to find them?

Just this year, a test is available that is accurate enough to measure anti-aging benefits on short time scales, without waiting for subjects to die. DNAm PhenoAge is a simple blood test developed at the lab of Steve Horvath. It determines risk of age-related mortality accurate to about 1 year of biological age. Averaging over just a hundred people pinpoints biological age with accuracy of one month. This implies that an anti-aging benefit can be detected with high reliability using a test population of just a few hundred people, followed for two years, tested at the beginning and end of this period. A study that might have required fifteen years and cost hundreds of millions of dollars can now be completed in two years at a cost of less than $1 million. When this new technology is embraced, we will have the means to separate the most effective treatment combinations from a large field of contenders.

The Mother of All Clinical Trials, Part II

Methylation isn't the only means by which gene expression is controlled - there are many others. But it is far the best-studied and, given present technology, it is the only epigenetic marker that can be routinely measured, for a few hundred dollars in a small sample of blood, urine, or nanogram-scale biopsy of other tissue. The clock was developed by Steve Horvath, and first published in 2013. He scanned the entire genome for sites that changed most with age, and varied least from one tissue type to another. In this way, he identified 353 sites, and optimized a set of 353 multipliers, such that multiplying levels of methylation at each site by each multiplier and adding the products produced a number that could be mapped onto chronological age.

Five years after Horvath's original publication, there are several other clocks based on methylation. Just this spring, Horvath has developed a new clock, not yet published, which, to my knowledge, is the best standard we have. This is the Levine/Horvath clock. It is based on 513 methylation sites and it is calibrated not to chronological age, but to a tighter measure of age-based health, derived from blood lipid profiles, inflammatory markers, insulin resistance, etc, which Horvath calls "phenotypic age". Consequently, it is less well correlated with chronological age than the original, but it is better able to predict mortality than either the classic Horvath clock or chronological age itself.

The original Horvath clock was developed by a statistical process that took into account only chronological age. But Horvath age turns out to be a better predictor than chronological age for risk of all the diseases of old age. This is powerful evidence that methylation is measuring something fundamental about the aging process. If an individual's methylation age is higher or lower than his chronologial age, the difference is a powerful predictor of his disease risk and how long he will live. This can only be true if methylation is associated with a fundamental cause of age-related decline.