A Review of the Intersection Between Aging Research and Calorie Restriction Research

Below, find linked a very readable review of the intersection between aging research and calorie restriction research. While less so now than a decade ago, it nonetheless remains the case that much of the ongoing research into aging is in fact not concerned with treating aging as a medical condition. It is observational only, an field of programs of investigation and mapping that are quite disconnected from any impetus to improve medical technology. In the other portion of the aging research community, however, the part of more interest to us, in which scientists are aiming at interventions that target the causes of aging, a sizable proportion of funding and initiatives can be traced back to roots in calorie restriction research. This is why this topic shows up so often here and elsewhere.

Interestingly, while interest in calorie restriction research is but a slice of the broader field of aging research, aging has always been a principle focus of calorie restriction research. This came to be an area of interest precisely because calorie restricted laboratory animals reliably live longer, a result first formally published by researchers some eighty years ago. That data languished until the era of genetics and molecular biochemistry arrived, at which point calorie restriction became a tool used to investigate the complexity of cellular metabolism: given two reliably produced states of metabolic operation, a great deal can be learned by looking into the details of the differences. In fact, judging by the behavior of the research community, we should probably consider aging to be viewed as a tool used to investigate the complexity of cellular metabolism. A great deal of the otherwise puzzling reluctance to engage with rejuvenation research, an engineering approach in which comparative ignorance of the progression of aging can be bypassed in order to apply what is already known of the molecular damage that causes aging, might be explained by presuming that most researchers are primarily motivated to produce a comprehensive map of our biochemistry, rather than to produce more effective therapies.

So, given the starting point of calorie restriction, researchers move along chains of cause and effect in cells, mapping proteins and their relationships, comparing old and young, calorie restricted and well fed states. Technologies are spun off as they can be from these investigations, because every research institution is these days embedded in a larger organization that seeks to apply new knowledge in any way possible, but this application is a secondary concern at the point at which new directions are chosen for aging research. Since the primary thrust of the work takes little account of the potential effectiveness of resulting technological applications, we end up with a great deal of effort devoted to developing calorie restriction mimetic drugs that might slightly slow aging, rather than that same effort devoted towards repair technologies capable of rejuvenating the old. This happens because the primary goal for researchers is gathering information about biochemistry, as opposed to bringing aging under medical control. In this, there is a set of fundamental mismatches between the expectations and goals of funding sources, researchers, entrepreneurs, and the public at large.

Aging and Caloric Restriction Research: A Biological Perspective With Translational Potential

The dramatic increase in average life expectancy has led to a rapid rise in the aging population across the globe. Age is a robust and independent risk factor for a range of non-communicable diseases like cancer, diabetes, cardiovascular disease, and neurodegenerative disease, and so it follows that this newfound increase in longevity creates a substantial burden in disease incidence and health care costs. Overwhelming evidence suggests that processes intrinsic to aging contribute to the pathogenesis of age-related diseases. Ongoing international efforts have made great strides in advancing our knowledge of the biology of aging and several “hallmarks” of aging have been identified that may play a causative role in the age-related increase in disease vulnerability.

These last few years have seen a shift in emphasis from the investigation of individual age-related diseases in isolation toward a broader context to define the basic biology of aging. The concept behind the recently coined pursuit of geroscience is that a strategy to delay the aging process itself would decrease vulnerability across the age-related disease spectrum leading to lower morbidity and comorbidity. Indeed the concept that aging might be a suitable drug target in a clinical context is gaining traction and there is considerable effort being applied to bring this idea to fruition. One of the most valuable tools in aging research is caloric restriction (CR), a proven intervention to delay aging and age-related disease. If we could understand what mechanisms are employed by CR to impinge on the aging process we could potentially identify causal networks that contribute to the increase in disease vulnerability as a function of normative aging.

To investigate the translatability of CR’s beneficial effects from rodents to primates, three independent rhesus monkey studies were initiated in the late 1980s. The take home message from this joint initiative is that CR delays aging in primates, where lower food intake is associated with improvements in health and survival. The implications of this work are broader, first that aging in primates can be manipulated, supporting the concept that aging is a valuable target for intervention and eventual clinical application, and second, that the mechanisms recruited by CR to impinge on aging will likely have utility in the development of treatments to delay or abrogate age-related disease vulnerability.

With evidence that CR is effective in long-lived species the next question is whether its beneficial effects and mechanistic underpinnings are conserved in humans. The hallmarks of mammalian CR include lower adiposity, increased insulin sensitivity, favorable lipid profiles, and increased levels of the adipose-derived hormone adiponectin. Short-term studies of CR in humans have been conducted as part of the multicenter study CALERIE in 2 phases. In the first phase of CALERIE studies (CALERIE-I), the metabolic effects of 6 or 12 months of CR was evaluated in overweight individuals with a target level of restriction of 20-30%. Favorable changes in body weight, body composition, glucoregulatory function and serum risk factors for cardiovascular disease were reported in CR individuals. These outcomes were consistent with those reported for monkeys on CR. Overall, these studies are highly suggestive that CR’s effect on aging is translatable to humans and confirm that nonhuman primates do indeed bridge the gap between human and rodent studies.

CR impinges on multiple signaling pathways that regulate growth, metabolism, oxidative stress response, damage repair, inflammation, autophagy, and proteostasis, to modulate the aging process. The relationship between calorie intake and longevity follows a U-shaped curve, dietary excess and malnutrition both negatively impact survival. Between the extremities there is an inverse linear relationship between lifespan and calorie/energy intake, suggesting that adaptive metabolism is a key component in the response to CR. Caloric restriction as an intervention is likely to be very difficult to implement in humans. Indeed the goal of CR research is to figure out how it works, not to promote it as a lifestyle. In order to gain the beneficial effects of CR without the restriction of calories, a number of nutraceuticals and established drugs are being explored as a means to mimic the effects of CR. The National Institute on Aging (NIA) has created the Interventions Testing Program (ITP) to investigate treatments with the potential to extend lifespan and delay age-related disease and dysfunction. To date several effective compounds have been identified some of which have been used in human clinical applications such as rapamycin (inhibitor of mTOR), metformin (activator of AMPK), and others that are only recently being applied in human studies such as resveratrol (activator of AMPK and SIRT1).

Aging research has entered a very exciting period where traditional scientific approaches to understanding the biology of aging are converging with clinical research and epidemiology. Technological advances in the last few decades have brought aging research to a place that could not even have been imagined back in the days when the establishment of the National Institute on Aging first officially recognized the science of aging. We have already seen the identification of genes and biomarkers associated with healthy aging and exceptional aging, and studies in laboratory animals have laid out a rich framework of factors that have established roles in regulation of longevity.

Outstanding questions include the molecular basis for the role of energy metabolism in aging. How do differences in mitochondrial function create vulnerability to disease? How do defects in mitochondrial efficiency and adaptation arise? To what extent do minor differences in energetic capacity or fuel utilization influence other cellular functions? What networks within the cell are responsive to these relatively small age-related changes? Another important avenue of investigation is the role of lipid metabolism in aging and disease vulnerability. Lipid transport and lipid handling are common themes in human and laboratory aging studies, and differences in lipid metabolism have been strongly implicated in the mechanisms of CR, but how does this translate to a change in disease vulnerability as a function of age?

Taking a broader view, it will be necessary to distinguish between events that are coincident with aging and those that are driving aging. Does aging arise first within discrete systems or is it orchestrated simultaneously across systems? To what extent are failures in individual processes such as repair or induction of senescence responsible for age-related disease vulnerability? To resolve these and other questions future directions must include synergistic collaborative efforts focused on aligning insights from human and laboratory aging studies. Caloric restriction research will also have a role to play, where interdisciplinary approaches can be brought to bear to determine the molecular details of CR’s mechanisms and thereby identify the most promising candidate factors for targeted intervention.

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