Fight Aging!

Both healthy and overall life expectancy has gently trended upwards over the last few centuries. In recent decades the pace has been two years per decade for life expectancy at birth, and perhaps one year every decade for life expectancy at 65. If we understand aging to be an accumulation of cell and tissue damage, and we understand that no past therapies have deliberately addressed this damage, then it is probably a fair question to ask why this trend in human life span exists. Is it an inadvertent slowing of damage accumulation, the result of somewhat papering over the consequences of that damage, or some other effect? The underlying reasons for small, slow changes in complex, poorly understood systems are ever challenging to pin down, especially when so much of the evidence is statistical in nature. This leaves a lot of room to debate, particularly regarding the nature of the present trend, rather than the century-old gains in life expectancy that were most likely due to reductions in the burden of infectious disease over the life span.

As a sidebar, the author of this paper, Thomas Kirkwood, is one of a number of scientists in the field who fully embrace the concept of aging as a process of damage accumulation, but nonetheless are either ambivalent or hostile towards efforts to repair the damage in order to create rejuvenation therapies. If you look back in the Fight Aging! archives, you'll find a fair number of examples of Kirkwood sparring with Aubrey de Grey of the SENS Research Foundation, or otherwise dismissing the SENS damage repair approach. Now that senolytic therapies to clear senescent cells are undeniably mainstream, a repair approach that was part of the SENS portfolio at the outset, Kirkwood must acknowledge it. Indeed, he does so in this paper. This is how progress is going in some parts of the research community: people who rejected SENS out of hand ten or fifteen years ago, despite the compelling evidence, continue to reject SENS out of hand, except for the one piece that they now cannot ignore.

During the last decades of the 20th century, a remarkable phenomenon became apparent. Contrary to general expectation, the increase in human life expectancy - a measure of average length of life within the population - that had been occurring steadily in developed countries for almost two centuries failed to hit its predicted ceiling and has carried on at the same rate as before. To appreciate why the continuing increase in life expectancy was unexpected, it is necessary to examine what had been driving its earlier increase: cleaner drinking water, better sanitation and improvements in housing, education and nutrition all contributed, aided latterly by the development and widespread application of vaccines, antibiotics and other advances in preventive and therapeutic medicine. As the last quarter of the 20th century began, the residual levels of early- and mid-life mortality had fallen so low that any further reductions could have had only a modest effect on further increasing life expectancy.

As it was assumed that the ageing process itself was essentially immutable - a biological given - it was expected that populations would simply contain greater numbers of older people. These would die at the same ages as the oldest of their predecessors, who had been fewer in number but aged just the same. What has changed, however, is that it is now the death rates of those of advanced age - 80 and older - that are falling fastest. Put simply, it seems that the nature of old age is undergoing a significant change. Old people are, as a rule, reaching more advanced ages in better and better condition, and this is reflected in the continuing increase in life expectancy. What is likely to happen to human longevity in the future? What factors influence our individual trajectories of health into old age? How feasible is it to think of discovering new ways to extend further the duration of healthy life free of disability and disease?

The evolution of ageing is now generally understood to have occurred not through programming of ageing as an adaptive benefit in its own right, but because the force of natural selection falls off strongly across the course of the lifespan. The different longevities of different species can be explained because the exposure to accidents varies from one species to another, and consequently, selection will favour a higher investment in somatic maintenance in a species better adapted to survive the hazards of its ecological niche than in a species subject to a higher extrinsic level of risk. Comparative studies of ageing consistently reveal that cell maintenance is greater in longer-lived organisms.

A striking feature of ageing is its variability. That ageing is malleable is evident from the falling death rates in old age. The more hygienic conditions of modern life in high-income countries, with fewer sources of physical stress and earlier interventions to maintain health, most probably explain why people now reach old age physically 'younger' than their parents and grandparents. Malleability is also evident through the social gradient in health and life expectancy, whereby those of lower socio-economic status have shorter life expectancy.

Recent progress in research on ageing has generated considerable interest in the potential for science to extend the human health span, i.e. the period free of significant disease or disability, beyond the improvements that are occurring already. These include the possibilities of the following: (i) drugs targeting molecular pathways found to be involved in the regulation of lifespan, such as rapamycin and resveratrol, or enzymes such as telomerase; (ii) control of food intake through dietary restriction or intermittent fasting, to mimic longstanding observations on the life-extending effects of caloric restriction in rodents; (iii) so-called 'senolytic' strategies selectively to remove senescent cells from aged tissues and organs; (iv) transfer of plasma or serum from young to old individuals, based on pioneering studies using pairs of young and old rodents whose circulatory systems were connected; (v) repurposing of existing drugs, such as metformin, previously licensed for treatment of diabetes and now of interest for potential anti-ageing properties.

Despite the exciting potential for progress, it is important to reflect briefly on the main challenges confronting the attempts to extend the health span. The regulatory framework within which new interventions to extend health span can be developed raises particularly interesting challenges. When targeting illness, especially if it is painful and life limiting, the barriers against accepting possible side-effects are lower. Thus, anti-ageing interventions will most easily gain approval if they target late-stage diseases. However, these are not the interventions that will most effectively extend the health span. The latter interventions are ones that would need to be introduced before or as soon as possible after the earliest signs of age-related health deficits become apparent. They will therefore also be candidates for application across the population at large.

It is as yet uncertain to what extent and when science will deliver improvements in health span. Given what we know already about the general nature of the ageing process and of its malleability, it seems entirely reasonable, indeed probable, that improvements of this kind will occur. It would be wise, however, not to promise or expect too much too soon. However, the same science is likely to provide further evidence to support and encourage the kinds of changes in nutrition and lifestyle that are already known to be effective, and here it is reasonable to expect benefits to occur faster.

Link: https://doi.org/10.1113/EP086205