Fight Aging!

Today I'll point out a recent collection of papers on calorie restriction from the Journals of Gerontology, including a report on the CALERIE human study in which algorithmic approaches to measuring biological age - constructing a measure from simple health metrics, such as the measures found in blood tests - indicate a slowing of aging in participants. Calorie restriction has been shown to slow aging in near all species and lineages tested to date, much more so in short-lived species than in long-lived species. Thus calorie restriction and methods of mimicking some of the cellular response to calorie restriction make up the present majority of initiatives among those scientists of the aging research community who have shown themselves willing to embrace the goal of treating aging as a medical condition. This encompasses investigations of mTOR, involving rapamycin and related compounds, slow steps towards any one of half a dozen approaches to autophagy enhancement, the long drawn-out dead end of sirtuin research programs, and many more lines of work.

Aubrey de Grey has called this a false dawn - a blossoming of research that accompanied a great change in the culture of the scientific community, as it transformed from a closed-mouth group whose members denied and discouraged all interest in treating aging, to one in which many researchers now talk openly and excitedly about extending healthy life spans. Yet they have largely settled upon a program of research and development, focused on calorie restriction, that cannot possibly produce sizable effects on human life span, and is in addition demonstrably expensive, slow, and challenging. It dovetails well with the urge to map metabolism in detail, however, which is perhaps why this field has expanded despite the poor prospects for benefits to health and longevity at the end of the day.

By any sensible cost-benefit analysis, the practice of actual calorie restriction is, like exercise, a great gift from our evolutionary history: a reliable and free way to improve long-term health to a greater degree than any presently available medical technology can achieve. It is a sound idea to adopt this proven approach as a health strategy; the evidence is compelling. A few additional years for free, and a lower risk of age-related disease? Sign me up. Yet spending billions and decades of researcher time to reproduce that in a pill? Not so great, when the alternative uses of that time and funding, such as pursuing the rejuvenation therapies of the SENS programs, could be expected to add decades of additional healthy years to our lives. The expected quality of the outcome matters greatly when choosing strategy, and currently most of the research community is choosing poorly.

In Delaying Aging, Caloric Restriction Becomes Powerful Research Tool as Human Studies Get Underway

The beneficial longevity effect of a simple reduction in calorie intake was first established in rodent studies more than 80 years ago. In the last few decades as genetic techniques have advanced, scientists have made considerable progress in identifying cellular and systemic processes that likely contribute to the increase in disease vulnerability that is associated with aging. Traditionally, these insights have come from studies of short-lived laboratory animals, but the recent confirmation of the relevance of the CR paradigm to primates has placed renewed emphasis on studies that delve into the mechanisms of delayed aging by CR. "Remarkably, caloric restriction has been shown to be effective in delaying aging in multiple species and the results in humans look equally promising. Indeed for many studies, CR is used as the gold-standard for enhanced longevity against which new drugs and anti-aging strategies are measured."

Caloric Restriction Research: New Perspectives on the Biology of Aging

The principle of geroscience is that aging itself is a worthy target for intervention: if aging can be offset then age-related vulnerability to diseases and disorders such as cancer, heart disease, frailty, and neurodegeneration, would be postponed and attenuated. If we could understand how CR exerts its effects to prolong health and delay mortality we will surely be able to identify key regulatory nodes involved in countering the causative factors in aging that lead to morbidity and mortality.

Within the last 10 years, the long suspected but previously unconfirmed demonstration that primate aging is indeed malleable came from studies of CR in rhesus monkeys. Over the course of that ~30-year study longitudinal biometric, physical activity, and metabolic data, were captured and used to evaluate the monkey model as a means to investigate frailty. The group showed clear differences between control-fed and CR monkeys. Further, the CALERIE study is the first human clinical trial of CR. Conducted across three sites in the United States, this pioneering work showed not only that CR could be tolerated in humans but it also produced beneficial effects on numerous clinical disease risk indices.

The search for agents that can exert the beneficial effects of CR without the requirement for a reduction in calorie intake has undergone considerable expansion over the last decade. Among these aptly named "CR mimetics" are resveratrol and metformin both of which have been shown to produce beneficial effects in rodents. Recent studies point to potential new applications for these CR mimetics as a means to counter skeletal muscle aging. Furthermore, they demonstrates the power for mechanistic discovery in the application of CR mimetics to uncover the biology of discrete factors within tissues that contribute to the aging phenotype.

Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis

Biological aging refers to the gradual and progressive decline in the integrity of the body's systems occurring with advancing chronological age. Rather than any specific disease process, this decline in system integrity is thought to reflect biological changes having their origins in aging itself. Whereas chronological age increases at the same rate for everyone, biological age can increase faster for some and slower for others. To the extent that geroprotective therapies modify basic biological processes of aging, their effects should be reflected in a slowed rate of decline in system integrity - slowed biological aging. Recently, several methods have been proposed to quantify biological aging using algorithms that combine information from multiple biomarkers.

Caloric restriction is among the oldest and most effective geroprotective interventions in worms, flies, and mice. Growing evidence suggests caloric restriction also benefits life span and healthspan in primates and humans. A unique resource to study effects of caloric restriction in humans is the 2-year randomized controlled trial of caloric restriction in young, non-obese healthy humans, Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy (CALERIE).

We analyzed CALERIE Biobank data to test whether recently proposed methods to quantify biological aging would prove sensitive to geroprotective effects of caloric restriction over the relatively short, 2-year span of the human trial. Tests using two different methods to quantify biological aging (Klemera-Doubal method Biological Age and homeostatic dysregulation) produced a consistent result: participants in the caloric-restriction arm of the trial experienced slowed biological aging as compared to participants in the ad libitum arm. Sensitivity analysis showed that slowed biological aging in the caloric restriction arm of the trial was not accounted for by weight loss during the intervention phase.

The main contribution of this study is to provide initial evidence that methods to quantify biological aging are sensitive enough to detect effects of geroprotective therapy delivered to middle-aged adults in a small randomized trial. This evidence argues for using methods to quantify biological aging as outcomes in trials of geroprotective therapies.