An Approach to the Analysis of Differences Between Species in the Matter of Aging and Longevity-Enhancing Interventions

Most research into the mechanisms of aging starts with cells and then moves to short-lived species such as flies or nematode worms - easier to manage than mice, and the short life spans mean that more work can be carried out for a given amount of funding and time. Only later do more promising projects move to the use of mice. At each stage of the process, from cells to worms, from worms to mice, from mice to people, many research results fail to prove relevant. Worms are not mice, and mice are not people. There are significant differences, for all that many of the most fundamental aspects of aging and cellular biochemistry are remarkable similar in all of these species. The paper here, the full text in PDF format only I'm afraid, is an interesting attempt to put some numbers to the degree to which nematodes and mice are different in the matter of aging and interventions that slow aging.

Given the existence of subtle but important differences that can produce the results outlined here, then it may well be the case that the development of reliable biomarkers of aging should be prioritized to a greater degree and work in nematodes and the like largely abandoned in favor of short mouse studies that assess effects on aging through the use of biomarker tests. The discussion below should be considered in the context of the comparatively small changes in life span achieved by most interventions, where it is reasonable to ask how that change came about and whether it was due to an influence on aging or some other factor. The future of the field, assuming that SENS rejuvenation research prospers, is to create increases in life span and health span so large that there is no room for debate as to what is taking place.

It has been argued that an extension of lifespan may not necessarily be concrete evidence of a retardation of the aging process. In this view, a lifespan-extending intervention may simply remedy deficiencies in the environment or in the genetic make-up of one particular strain. The intervention would therefore extend lifespan by correcting specific flaws rather than altering the aging process. These considerations create a conundrum: if lifespan is not a reliable measure of aging, how can we confirm that a particular manipulation truly affects the aging process? One approach is to assess physiological phenotypes which are known to deteriorate with age, such as cognition or the functioning of the cardiovascular or immune systems, in order to detect similarities or discrepancies with the patterns observed in control strains. An alternative criterion is to consider whether a particular manipulation changes how mortality rates increase with age. This is based on the hypothesis that the increased incidence of the age-related pathological changes that characterizes the aging process is reflected in changing mortality rates.

In the Gompertz model of mortality, 'G' describes the rate at which mortality rates accelerate with age and 'A' represents the initial mortality rate at time 0. 'A' is strictly theoretical as a mortality rate, since there can be no actual mortality at time 0. Instead, it can be determined by extrapolation from mortality rates at greater ages, and does not necessarily correspond to true mortality rates at birth or during youth. Decreasing 'A' extends lifespan by shifting the inflection point of the curve rightwards, such that it occurs proportionally later in age, relative to maximum lifespan. There is no change in the apparent "slope" of the curve. In contrast, decreasing 'G' extends lifespan by decreasing the slope. 'A' has been described as measuring the vulnerability to disease unrelated to the onset of aging, or the effect of the environment on mortality. Changes to 'A' will alter mortality rates evenly across the lifespan of the population. In contrast, since the parameter 'G' can be considered a rate constant for the age-related increase of mortality of a sample or population, it is often given a pre-eminent role as an indicator of the "rate of aging". This is a logical hypothesis, since an increased or decreased 'G' would likely reflect the rate at which physiological conditions are declining with age. Therefore it is often assumed that interventions that extend lifespan by slowing aging, rather than by alleviating some age-independent pathology, will be associated with a decreased 'G'.

Since a substantial number of studies reporting changes in mouse lifespan resulting from genetic manipulations have now been published, we hypothesized that a correlation-based approach may be a more powerful technique to search for patterns in Gompertz parameter shifts. For example, a negative correlation between lifespan and 'G' across long-lived lines of mice would suggest that their extended longevity was due to a decreased rate of aging. By the straightforward method of plotting Gompertz parameters against lifespan we found that most of the genetically-driven variability in lifespan between normal- or long-lived groups of mice was due to changes in 'A', not in 'G'. In fact, 'G' remained remarkably invariant for different groups of wild-type mice as well as for mice with genetic variations that extend lifespan. The only exceptions to this trend were some interventions which acutely shortened lifespan. We also found this to be true for a collection of inbred mice strains studied under uniform conditions as part of the Mouse Phenome Database. Thus, with the exception of some severe lifespan-shortening interventions, lifespan in laboratory mice is largely determined by factors that affect initial vulnerability, rather than age-dependent mortality rate acceleration. In contrast to mice, we found lifespan to be associated with changes in 'G', not 'A', among long-lived C. elegans mutants. This was true as a trend across long-lived mutants, and was also observed by analysing changes to Gompertz parameters among numerous replicate studies of the well-characterized daf-2, isp-1, and eat-2 mutants.



These results seem to actually suggest that because of a closer link to changes in G rather than A, C. Elegans is actually a better model for studying aging interventions. Most of the major calorie restriction-linked aging and longevity genes which have been studied, such as igf-1 and foxo3, were originally linked to aging through their nematode counterpart, and it's notable that the only intervention that this study finds which constitutes a change in G in mice is calorie restriction.

That being said, as someone who works in a C. Elegans lab I agree that they have outlived their usefulness to some degree in studying the genetics of aging. It'd be interesting to discuss what benefits they may have from a SENS style intervention standpoint though. Although repairing for example glucosepane in worms would tell us little about the longevity benefits in humans (worms don't even have blood vessels), worms are very very cheap and easy to use and may lend themselves well to initial tests for pure crosslink breaking efficiency (if they don't naturally accumulate glucosepane you could probably find a mutant/model which does). This is just theorizing, but it could be generalized to lysosens, mitosens, and maybe amylosens, as well as treatments related to transposons/progerin/DNA damage, etc.

Posted by: Kris at September 21st, 2016 11:12 AM

Kris said: "These results seem to actually suggest that because of a closer link to changes in G rather than A, C. Elegans is actually a better model for studying aging interventions."

Well, it depends on what "better" means. If it means "better for finding treatments for humans", then they probably aren't. Thus, the paper would imply that all these candidate interventions will fail in humans like they failed in mice.

If it means "better for finding treatments for retarding aging in some animal, no matter which animal" then yes, they are better.

Posted by: Antonio at September 21st, 2016 2:49 PM

Hi !

In the study they said :

In short-lived mice the correlation of 'G' with lifespan approached statistical significance (Figure 2A; r = -0.47, p = 0.06). However, this was largely due to the two shortest-
lived lines (Klotho and Lmna mutants), with median lifespans less than two months (if they were excluded, r = -0.22, p = 0.46). These two lines also had by far the largest 'G' (22 and 61, respectively, as compared to a median value of 3.3 for short-lived mice).''

This means that their study is mostly flawed and that thus, mice, like C.elegans are under the G too, wether short-lived or long-lived.
It is rather ironic that they did not add the naked-mole rat or other much longer-lived rodent, at least they added a much shorter-lived mouse
like the SAMP8 mouse (senenscent accelerated prone mouse), and they did, then, see that G was important and correlative.

Wild C.elegans have a morbidity window of 10 days, no matter if short-lived or long-lived (as in the age-1 (mg44) F2 longest-lived C.elegans mutant ever at 180-250 days maximum lifespan). In fact, at 10-fold longer lifespan, morbidity is down to 5 days even (cut by 50%, thus even more compression).
Thus for wild C.elegans that is nearly a third of their life, while for longest-lived mutant (much more than daf-2) it is less than 4% of its life. Demonstrating great morbidity lengthspan peroid compression with lifespan extension but the window stays the same.
As for the rate of morbidity acceleration rising curve, in the last 10 days morbidity rate acceleration rises many folds in a progressively higher/upwards ('to death') fashion.

Had they compared their study with naked more rats they would have found that indeed G is the main decider, as was shown in short-lived mice.
In ancient times, for humans, A was the decider, because humans died prematurely from diseases or were killed in the hunt at 20 or 30 years old.
Now that doesn't happen anymore, vulnerability in young age has no say, because there is no more vulnerability (you don'T die young anymore, you live longer, no more extrinsic dangers),
thus G is now more applicable and it's aging in the sense of mortality acceleration and window morbidity compression at very high age, and even more at extreme ages like centenarians.
Humans have a morbidity period (from transcriptional drift) starting at 60 years old and all the way to 100 years old, this drifting is immense/greatly accelerated morbidity in the last decade before 100.
After that, any moment you could die suddenly in your sleep because the drift is so far off that your system is totally 'gone' and surprisingly 'still' working (at 100+). Women that reached 110, 115, 120 had delayed this drift by a decade, same for men in their 100s.
Thus, if humans lived 500 years, the same would apply, their transcriptional drift would have been conversed 'frozen undrifting state' for the better part of 450 years, and the last 50 years preceding 500 would have dramatic mortality increase, all the way up to 490 before 500, where the last decade would be akin to 90-100 year decade.
This means the mortality curve would be extremely 'flat' and then rise sharply in the last 49th decade before 50th decade (500). There would not be a curve, where humans living over MLSP 122, have a very elongated by slowly rising curve over 300 years. No it is a curve that rises in the last 40 years the human lifespan. Every other extra year is an 'extra year' to the life span, meaning if you have 500 extra years to your life, you will not age for 300 or 400 years with a progressive rising curve; it's impossible.
Those extra-years are what I call the 'young years' you will simply post-pone transcriptional drift as long as needed, that means staying in a state of non-drifting (which is about 20 years old in biological age), which means you would stay 20 years old biologically for at least 440 years; and then morbidity would increase dramatically in that 460 to 500 window. It is impossible to reach 500 years anyother way because transcriptional drifting doesn't allow it/neither damage accumulation in concert.

This can be proven by the fact the longest living aquatic animal on Earth, the A.Islandica quahog clam at 528 years old MLSP, as redox maintenance for as long at that time; and one study showed that
transcriptional drifting is direct correlation to redox maintenance, meaning as it drifts so does the redox. A 500 year lifespan clam does not drift epigenetically/transcriptionally because its redox is maintained for at least 192 years, it then lives 500 years. This is the same thing that will happen for humans if they which to reach that age.

Posted by: CANanonymity at September 21st, 2016 5:04 PM

@Norse It's not a wiki per se but is kinda like a wiki.

Posted by: Anonymoose at September 22nd, 2016 3:01 PM

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