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Why and How are We Living Longer?

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

Comments

Nicely done, it's heartening to know that perhaps there *is* some debate out there with respect to damage-repair versus other methodologies.

But I'm having trouble believing the following to be true:

"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."

I would think that a 90-year-old receiving, say, an effective senolytic treatment, would actually have a more dramatic, visible change in their health, than would a 60-year-old who receives the same treatment. And also, year-by-year, that 90-year-old's health would be of a more keen-interest to the public...b/c you have the dramatic effect of "saving their life", in essence..since there's so much risk at that point, and so little time (compared to 60)...

If you're talking about measuring a biomarker (gosh I hope!) before-and-after, then my intuition says that the potential rejuvenation is *vastly* larger with a 90-year-old than a 60-year-old...or no? What am I missing?

thanks!
Euge

Posted by: Euge at August 7th, 2017 9:17 AM

@Euge
You're a number of things.
The interplay between factors and the feedback loop nature of aging.
The older you are the more things (quantity) that need fixing and the more (quality) they need to be fixed.

Clearing the senescent cells of a 50 year old cyclically might well enough be just right to slow down the development of such conditions like arthritis and osteoporosis significantly.

In contrast in a 90 year old they might give relief from inflammation but nothing more because many more problems have reached critical mass at that point and simply removing senescent cells won't revert the damage done either.

It's one of the more astute observations Kirkwood has made to date.

Posted by: Anonymoose at August 7th, 2017 9:48 AM

You're a number of things. = You're MISSING a number of things.

I type too fast for my own good sometimes.

Posted by: Anonymoose at August 7th, 2017 9:49 AM

"During the last decades of the 20th century, a remarkable phenomenon became apparent. Contrary to general expectation, the increase in human life expectancy [...] 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."

There was no reason at all to be surprised, since the change ocurred around 1950, not 2000.

https://s1.postimg.org/jsgbjuk19/sweden.png

Posted by: Antonio at August 7th, 2017 10:11 AM

An older person has been more damaged by the other hallmarks of aging. This is why Aubrey and others have said just one intervention isnt going to achive a great deal. It will improve things but as the rodent data shows just tackling one hallmark does not stop the others killing them.

One of the reasons we published an article about being too optimistic:

http://www.leafscience.org/optimistic-but-not-complacent/

Posted by: Steve Hill at August 7th, 2017 10:27 AM

Thank you all for your insight.

I agree that a 90-yr-old has been damaged more, is more likely to die sooner because of other hallmarks having their deleterious effects, and also that it would be easier to rejuvenate a 60-yr-old.

However, the reason I was offering the idea of the 90-yr-old was due to the major issue we have with Approval (which is a roadblock which could be a disaster, I would think):

"anti-ageing interventions will most easily gain approval if they target late-stage diseases"

If he is correct, then we need a solution to do this very thing...gain approval. Target the 90-yr-old and his disease...and cure it. Yes, he will still unfortunately suffer from the other Hallmarks...but you've now gained a precious thing...Approval and proof, while rolling-out medicine with an acceptably-higher-probability of side-effects, as well.

How do we propose getting around this Approval roadblock other than that? Do we think the metformin trials count as a good effort for this challenge?

(All these have the condition listed as "Aging", fwiw)

https://clinicaltrials.gov/ct2/show/NCT03072485?term=metformin&recrs=a&cond=aging&rank=2
https://clinicaltrials.gov/ct2/show/NCT02308228?term=metformin&recrs=a&cond=aging&rank=1
https://clinicaltrials.gov/ct2/show/NCT02745886?term=metformin&recrs=a&cond=aging&rank=3

Euge

Posted by: Euge at August 7th, 2017 11:42 AM

I read somewhere that your chance of dying doubles every 8 years, so the 90 year old is in much more serious risk of mortality than the 60 year old. However, the older you get, the higher your life expectancy is. A 75 year old man would have a 50% chance of dying by 87, whereas a sixty year old man has a 50 % chance of dying by 82.

Posted by: Biotechy at August 7th, 2017 2:42 PM

Could one of the explanations for increases in late in life longevity simply be that the wear and tear of day to day human labor has decreased significantly starting in the post WWII period - meaning that people "wear out" later than they used to, along with more real medicine (there truly wasn't much actual medicine in 1945) and the "social vaccine" effect of lawsuit and politically driven safety innovations (EPA, FDA (food safety), seat belts).

Posted by: David Gobel at August 8th, 2017 8:59 AM

My personal experience tells me that there is little to no hope for turning around the avg middle American as far as aging.

They have been worn down by working all their lives for the man...buying the foods and products they are told to buy....then expecting Big Med to fix them. Many are obese with arthritis and have no clue about diet...let alone supplements and exercise. They really have no clue.

I really think they are aging faster than their/my parents.

The only one of my siblings and relatives that has gotten a clue is my sister-in-law who has stage 4 breast cancer. Who knows how that will go....

For myself I do what I can to slow aging and square the curve...but I still expect to follow the typical pattern I see...typical 70s....typical 80s...90 if I am lucky or maybe unlucky?

Just hope to make it as far as I make it still able to think and be mobile. So...get on with that Sens thing would you....

The ones who don't make much effort will fall along the way?

Posted by: marvin at August 16th, 2017 10:20 AM

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