The practice of calorie restriction has been shown to reliably and robustly extend life in a variety of species. It has been used for decades now as a tool to investigate the relationships between metabolism, genetic variation, cellular biochemistry, and aging. Does the life extension produced in response to calorie restriction mean that it slows aging, postpones aging, or both? What does the distinction between slowing and postponing aging even mean at the most detailed level of consideration? Attempting to answer this question means engaging with definitions of aging, whether statistical or physiological, that are all still fairly open to debate. This is well illustrated by the open access paper linked below.
Over the past twenty years researchers have discovered and demonstrated many interventions that extend healthy, mean, and maximum life spans in varied combinations and degrees in short-lived species such as nematode worms, fruit flies, and mice. The plasticity of life span in response to altered environmental, genetic, and metabolic states is inversely related to the unmodified life expectancy of the organism in question. The longer the life span, the less it changes. So while nematodes that normally live for a few weeks have been engineered to gain as much as a tenfold increase in length of life, in mice that normally live a few years the record for artificial life extension stubbornly remains stuck at the 60-70% increase achieved more than a decade ago. The researchers involved used genetic knockout of the growth hormone receptor, and by good fortune there is a small human population descended from a comparatively recent ancestor who have inherited a very similar loss of function mutation. They, much as expected, don't seem to have any obvious gain in life expectancy. We are a long-lived species in comparison to mice, and therefore our plasticity of life span in response to these sorts of alterations is much lower.
Why does plasticity of longevity scale in this way? Calorie restriction may provide the answer. The calorie restriction response most likely evolved very early in the history of life because it provides survival advantages in periods of famine. Famine takes place on seasonal or shorter time frames, and a season is a sizable chunk of the life of a mouse, but much less so for a human. Thus only the mouse evolves the ability to greatly extend life when calorie intake falls, despite the fact that both mice and humans exhibit quite similar short-term alterations in metabolic state in response to calorie restriction. Calorie restriction in mice can extend life by 40% or more, while in humans it certainly doesn't produce anywhere near that gain. There is no rigorous estimate for longevity added in humans practicing calorie restriction, and such an estimate is unlikely to emerge any time soon, but the much less rigorous process of theorizing and modeling suggests 5% as a reasonable ballpark. Anything much larger than that would appear as a strong statistical signal in many historical data sets that are known to show no such signs.
It is worth bearing in mind that when we seek to build therapies to treat aging as a medical condition, to bring it under control, the ideal goal is to postpone it, not slow it. A therapy that can postpone aging is a therapy that can be reused later to postpone aging some more. A therapy that only slows aging has no such option: it has a flat maximum benefit to life span. Postponing aging, provided it works well enough and doesn't let any aspect of aging leak though to accumulate, has an unlimited upside in terms of the years of healthy life it can add. This is one of the reasons why I'm very focused on repair of damage after the SENS model as the path ahead for the treatment of aging. Repair of the forms of cell and tissue damage that cause aging can in principle produce rejuvenation and indefinite postponement of aging, provided it can be made comprehensive enough. In comparison, work aimed at modestly slowing aging by developing drugs to beneficially alter metabolic state, meaning slowing the pace at which damage accumulates rather than repairing existing damage, has no such upside and will be of very limited utility to people who are already old and damaged.
Extensive experiments have demonstrated that caloric restriction and genetic disruption of growth hormone signaling can profoundly counteract aging in mice. Caloric restriction - or dietary restriction - is an environmental intervention, whereby the usual ad libitum dietary intake is limited to an intake of 30-40% less. Mice subjected to caloric restriction can live up to 60% longer, suffer less often and at higher ages from age-associated disorders, and exhibit less molecular stress and damage. Disruption of growth hormone signaling is a genetic intervention, whereby the production of growth hormone-releasing hormone, growth hormone, or the receptor of growth hormone is impaired, so that the effects of growth hormone are annulled. Mice with disrupted growth hormone signaling can live up to 70% longer, suffer less often and at higher ages from age-associated disorders, have youthful metabolic characteristics such as a higher insulin sensitivity, and have an enhanced resistance against molecular-genetic stress and damage.
However, since age-dependent survival and life expectancy do not reveal at which ages and to what extent the risk of death increases, they conceal the effects on aging. Age-dependent mortality rates are generally fitted to the Gompertz model, after which they increase linearly with age on a logarithmic scale. The linear increase of such a modeled mortality rate is classically interpreted as an aging rate. However, the use of the Gompertz model constrains mortality rates to increase linearly on a logarithmic scale, which may not correspond with the increases in the crude age-dependent mortality rates, especially in relatively small populations. Therefore, alternative methods are needed to accurately examine the effects of interventions such as caloric restriction and genetic disruption of growth hormone signaling on age-dependent mortality rates.
According to the classical method, these interventions negligibly and non-consistently affected the aging rates. By contrast, according to the alternative method studied here, the aging rates of mice subjected to caloric restriction or disruption of growth hormone signaling increased at higher ages and to higher levels as compared with mice not subjected to these interventions. A key question in research on aging is whether increases in life expectancy reflect a postponement or a slowing of aging. The answer to this question is pivotal to gain insight in the mechanisms of aging, to identify interventions that modulate these mechanisms, and to predict the effects of such interventions on aging. However, with respect to caloric restriction and disruption of growth hormone signaling, a clear answer to this question is lacking. While caloric restriction has long been assumed to slow aging, it is debated whether it postpones aging instead. Likewise, some presume that genetic disruption of growth hormone signaling slows aging, whereas others pose that it rather postpones aging.
Our method interprets these interventions to affect the aging rates in an age-dependent manner: aging was slowed at lower ages, postponed until higher ages, but quickened at higher ages. Such a pattern resembles a compression of aging, whereby aging is postponed as well as intensified, reflected by a risk of death that increases sharply at a high age. A compression of aging also becomes apparent from the life expectancies of the mice: these interventions bring about an increase in median life expectancy that is two to four times larger than the increase in maximal life expectancy, indicating a sharper increase in the risk of death at a higher age. This effect was shared by caloric restriction and genetic disruption of growth hormone signaling. This conclusion warrants a reevaluation of previous studies on the effects of these interventions on murine aging with the use of the alternative method.