Fight Aging!

The latest analysis of data on primate longevity under conditions of calorie restriction was published today, and sides with the claims of extended longevity and improved health made a few years ago. Two long-running studies of calorie restriction in rhesus macaques commenced in the late 1980s and early 1990s, and are currently in the phase at which survival data can be discussed rather than projected. Rhesus macaques are known to have lived for longer than 40 years in captivity, but most in these circumstances die by age 35, and the average age at death is 26. This is an exceptionally long time to run a study in the modern scientific community. The cost of such studies is large, and in the present environment they are unlikely to be repeated or expanded upon in the foreseeable future. Firstly because we are entering the era of rejuvenation therapies, in which methods of modestly slowing aging such as calorie restriction will soon become irrelevant. Secondly, because there has been considerable debate in the past few years over the design of these studies, whether the results to date in fact illustrate that longer-lived primates exhibit extension of life span under calorie restricted conditions, or indeed, whether or not the results are actually useful given the issues with the studies. Still, if we want the data we are unlikely to find other sources any time soon.

An important point to keep in mind while considering this topic is that short-lived species have a greater plasticity of longevity in response to environmental circumstances, such as a lower calorie intake, and most likely to any gene therapy or pharmaceutical that mimics aspects of those environment circumstances. We know this because the practice of calorie restriction does not reliably produce 110-year-old humans, while in mice calorie restriction reliably extends life by as much as 40%. Why does this difference exist? From a molecular biology perspective it is puzzling given that the short-term changes in metabolism that take place under conditions of calorie restriction are remarkably similar in mice and people. From an evolutionary perspective, on the other hand, there is a solid theoretical explanation: calorie restriction, which evolved very early in the development of life, is a response to seasonal famine. It is a way to increase the odds of survival in an environment of scarcity that tends to last only so long. A season is a lengthy fraction of a mouse life span, but not so for humans, and so only mice experience the evolutionary pressure that leads to a proportionally large extension of life in this scenario.

Running studies in primates that live for decades is a way to try to understand to what degree we should expect calorie restriction to extend life in humans, and perhaps also to understand something of the mechanisms that ensure the outcome is a lesser degree of life extension than in short-lived mammals. Were there large communities of human practitioners of calorie restriction, the studies would not have taken place: researchers would do exactly what they do for, say, the effects of exercise, and first turn to human epidemiological data. There are, however, very few people with the necessary decades of calorie restriction behind them, so it is hard to answer questions about human long-term outcomes. The biomarkers and human studies of a few years or less suggest large benefits in terms of resistance to age-related disease, but again, there is a noted absence of effects large enough and reliable enough to show up in established databases of mortality and disease. Given the small number of practitioners, it is not entirely unreasonable to expect an effect of five to ten years to be hard to find in existing data, but much larger than this and we must start to question the plausibility.

The open access paper quoted below is very readable, and actually goes into some detail regarding differences between the studies relevant to past disputes over results. If the topic interests you, then you should certainly look over the whole thing rather than just the summary here. Does this new study add good reasons to practice calorie restriction? I'd say probably not on the whole. If you are not already sold on the rapid and sizable beneficial effects to health that are produced via a calorie restricted diet, or at least sizable in comparison to what any widely available medical technology can do for basically healthy people today, then I can't imagine that the endorsement here will be much of an additional attraction. It is one more data point atop a large and compelling mountain of data points. Being healthy for the long term does require some effort, and that will continue to be the case for a while yet. Being rescued from aging and ill health by progress towards rejuvenation therapies may indeed happen, but when it will happen is a question mark. So why shorten the odds for your own future by letting things go today?

Caloric restriction improves health and survival of rhesus monkeys

A clear understanding of the biology of ageing, as opposed to the biology of individual age-related diseases, could be the critical turning point for novel approaches in preventative strategies to facilitate healthy human ageing. Caloric restriction (CR) offers a powerful paradigm to uncover the cellular and molecular basis for the age-related increase in overall disease vulnerability that is shared by all mammalian species. CR extends median and maximum lifespan in most strains of laboratory rodents and also delays the onset of age-related diseases and disorders. Lifespan is also extended by CR in most short-lived species, including the unicellular yeast, nematodes and invertebrates. There has been rapid progress in identifying potential mechanisms of CR utilizing these models. These short-lived species are well suited for the investigation of the underlying mechanisms of CR due to the relative ease in their genetic manipulation, extensive genetic and developmental characterization, low cost, and significantly reduced timeframe for completion of longevity studies. A key question underpinning this body of work is whether the biology of CR, and its ability to delay ageing and the onset of disease, applies to humans and human health.

To date three independent studies of rhesus monkeys (Macaca mulatta) have tackled the question of translatability of CR to primate species. The University of Maryland rhesus monkey study was the first to report a positive association of CR with survival with a 2.6-fold increased risk of death in control animals compared to restricted. The primary focus of the study was not CR however, and analysis was based on comparing 109 ad libitum fed males and females from colony records at that facility, including insulin resistant and diabetic animals, to only eight male CR monkeys. Two other studies focused specifically on the impact of CR in healthy male and female rhesus monkeys: one at the National Institute on Aging (NIA) involving 121 monkeys; and the other at the University of Wisconsin Madison (UW) with 76 monkeys. The same statistical team was engaged for analysis of data from both studies. The UW study has reported beneficial effects of CR, including significant improvements in health and age-related survival, and all-cause survival. In contrast, the NIA study reported no significant impact of CR on survival, although improvements in health were close to statistical significance. The basis for the contrasting outcomes from these two parallel studies has not been established. Analysis of limited published bodyweight data indicated that the controls were not equivalent between the two studies, pointing to fundamental differences in study design and implementation. Therefore, to more fully assess possible explanations for the discrepant findings between the two studies, we have conducted a comprehensive assessment of longitudinal data from both sites highlighting differences that may have contributed to the dissimilar outcomes.

Data from both study locations suggest that the CR paradigm is effective in delaying the effects of ageing in nonhuman primates but that the age of onset is an important factor in determining the extent to which beneficial effects of CR might be induced. In the UW study, reduced bodyweight, reduced adiposity and reduced food intake of the CR monkeys were associated with improved survival, with CR monkeys of both sexes surviving longer than controls, ∼28 and ∼30 years of age for males and females respectively, and longer than the median age for monkeys in captivity (∼26 years of age). Although an impact of CR on survival was not detected within the NIA old-onset cohort, comparison to the UW study shows that bodyweight was significantly lower in both control and CR groups of males and females than in their UW control counterparts, and was largely equivalent to that of UW CR. All males and females from the NIA old-onset groups consumed fewer calories than their counterpart controls from UW, instead both control and CR were closely aligned with food intake values of UW CR.

Importantly, the median survival estimates for old-onset males were very high, similar to what has been reported previously as the 90th percentile for this species (∼35 years of age). Six of the original 20 monkeys have lived beyond 40 years of age, the previous maximal lifespan recorded, and one old-onset CR male monkey is currently 43 years old, which is a longevity record for this species. Median survival estimates for old-onset females, ∼27 and ∼28 for controls and CR respectively, were also greater than national median lifespan estimates, with one remaining female currently 38 years of age. The clear benefit in survival estimates for monkeys within the old-onset cohort compared to UW controls suggests that food intake can and does influence survival. The lack of difference between control and CR old-onset monkeys suggests that a reduction in food intake beyond that of the controls brings no further advantage. The minimum degree of restriction that confers maximal benefit in rhesus monkeys has not yet been identified but is an active topic of investigation. Taken together, data from both UW and NIA studies support the concept that lower food intake in adult or advanced age is associated with improved survival in nonhuman primates.

The catalogue of pathologies identified in aged monkeys is shared with aged humans. The definitions used to identify morbidity were determined by veterinary staff and were essentially equivalent at both sites. A shared feature of both studies is the beneficial effect of CR in lowering the risk for age-related morbidity by more than two-fold. The beneficial effects extended to diseases that are among the most prevalent in human clinical care including cancer, cardiovascular disease and parameters associated with diabetes. A lower incidence of cancer was one of the first health benefits of CR documented and is considered to be a hallmark of CR in rodents. The incidence of cancer was lower in CR monkeys at both locations indicating that tumour suppression is a conserved feature of mammalian CR. CR also lowered the incidence of cardiovascular disorders at UW, and NIA monkeys from either diet group appear to have been protected compared to UW control monkeys.

Given the obvious parallels between human and rhesus monkey data, it seems highly likely that the beneficial effects of CR would also be observed in humans. Reports from the multicenter CALERIE study of short-term CR in humans document changes in bodyweight, body composition, glucoregulatory function and serum risk factors for cardiovascular disease in response to CR. These outcomes in humans align well with reports on rhesus monkey CR, confirming that the primary response to CR is conserved between these two species, and suggesting that the underlying mechanisms may also be conserved. In conclusion, the NIA and UW nonhuman primate ageing and CR studies address a central concept of relevance to human ageing and human health: that the age-related increase in disease vulnerability in primates is malleable and that ageing itself presents a reasonable target for intervention. The last two decades have seen considerable advances in ageing research in short-lived species and investigations of the mechanisms of CR have been prominent in this work. It will be particularly informative to determine the degree to which consensus hallmarks of ageing described in recent publications also manifest in primate ageing. The tissues and longitudinal data stored over the course of these two highly controlled monkey studies present a unique resource that can be used to identify key pathways responsive to CR in primates, to uncover primate-specific aspects of the basic biology of ageing, and to determine molecular basis for nutritional modulation of health and ageing. Processes impacted by CR would be prime targets for the development of clinical interventions to offset age-related morbidity, and identification of factors involved in the mechanisms of CR will be pivotal in bringing these ideas to clinical research and human health care.