The Quest to Measure Human Biological Aging

Today's open access review article is a discussion of the importance of being able to measure biological aging, easily and robustly. Initially, this is an approach to speed the development of rejuvenation therapies; at present one can only efficiently and quickly assess the results of a potential rejuvenation therapy in the context of its ability to reverse a specific age-related disease. There are scores of important age-related conditions to assess, and animal models of these conditions are usually significantly different from the human condition - different enough for a careful consideration of the details to be needed to determine whether or not the model is useful.

If one wants to assess the overall efficacy of a rejuvenation therapy rigorously, it remains the case that life span studies are the only recourse. At minimum, deliver the treatment to old mice and run the study for six months to a year to see how mortality differs between the treatment and control groups. This is painfully expensive, and just doesn't scale to a world in which the research and development community may want to assess hundreds to thousands of variants of potential rejuvenation therapies at any given time. What is desired here is a way to run a quick study in normal aged animals: take a baseline assessment of the state of aging, deliver the intervention, and then within a week or two redo the assessment to see what has changed.

At present a number of different approaches to the measurement of biological aging are under development to one degree or another. The epigenetic clock is one such approach, which looks for epigenetic reactions to the underlying damage of aging. In this case, the challenge is connecting the epigenetic alterations characteristic of aging back to the underlying processes of damage and dysfunction: it is far from clear that the present clocks measure all of aging, versus part of aging. Another approach would be to take the list of cell and tissue damage that causes aging and measure each portion of it. Until rejuvenation therapies based on repairing this damage are developed, however, it will remain unclear as to the relative contribution of each form of damage to the progression of aging. Further, few of these forms of damage can actually be measured in a practical, non-invasive fashion in human patients. There is much work yet needed here.

Measuring biological aging in humans: A quest

Substantial investment is necessary to develop an estimator of biological aging that is robust, precise, reliable, and sensitive to change. Thus, a fair question is whether such a titanic project is worth the effort and cost. The answer is YES, without hesitation. Developing an index of biological aging is perhaps the most critical milestone required to advance the field of aging research and, especially, to bring relieve from the burden of multimorbidity and disability in an expanding aging population. Ideally, these measures would be obtained by running tests using blood samples without performing a biopsy, preferably quickly and at low cost.

An index of biological aging could be used to empirically address the geroscience hypothesis: "Is biological aging is the cause of the global susceptibility to disease with aging." Data collected longitudinally - ideally in a life course epidemiological study - could then be used to test if individuals that accumulate coexisting diseases faster than in the general population also have accelerated biological aging. Similarly, these data could be used to test if individuals who are biologically "older," independent of chronological age, are at a higher risk of developing different medical or functional conditions that do not share physiological mechanisms. Once validated, the fundamental basis of biological aging can be used to probe deeper into questions related to the mechanisms of aging, such as the following: Are there genetic traits that are associated with faster or slower biological aging? Are there "hallmarks" that are better at capturing biological aging at different stages of life?

Developing a proxy measure of biological aging for humans still requires work but is a very dynamic and promising area of investigation with strong potential for translation. Some of the measures - namely mitochondrial function, DNA methylation, and, to a lesser extent, cellular senescence and autophagy - are ready to be implemented based on several epidemiological studies, although refinements are always possible. Measures of telomere length are hampered by noise and wide longitudinal variations that cannot be explained by health events and at this stage are not useful for measuring biological age. New methods are being developed, some of which are focused on detecting the DNA damage response (a typical marker of critical telomere shortening) may yield better results. Senescence has been studied successfully in T lymphocytes, skin, and intramuscular fat, and high-throughput methods will be available soon. In addition, specific patterns of circulating proteins may exist that indirectly estimate the burden of senescence. Similarly, measures of autophagy are routinely used in mammalian studies and should be applicable to humans.

Multiple lines of evidence suggest that the measures listed above are associated with the severity of multimorbidity but, except for the epigenetic clock, this association has not yet been clearly established. Logically, none of the measures described above represent an exhaustive measure of biological aging and, therefore, new aggregate measures are needed that leverage differences and complementarities of the various biomarkers. To accomplish these goals, the hallmarks of aging should be assessed in a group of individuals that is reasonably sized and enough dispersed across the lifespan to represent the variability of biological age in the general population. Initially, it will be important to evaluate the intercorrelation between these measures.

These questions have immense relevance for geriatric medicine. Despite the rising emphasis on prevention, most current medical care is dedicated to diagnosing and managing diseases that are already symptomatic, which does not address the underlying issues related to geriatric health conditions. By understanding the intrinsic mechanisms of biological aging, including damage and resilience, medical professional will be able to best orient and prescribe therapeutic choices.

Progress in research is not linear. Periods characterized by rates of incremental knowledge are interlaced with "eureka" moments as milestone discoveries suddenly open new possibilities that thrust research and knowledge to a higher level. Galileo's use of the telescope to explore the stars, Kary Mullis's description of polymerase chain reaction, and Edwin Hubble's demonstration that the universe is expanding are just few examples of these moments. The field of aging research is living one of those magical moments. Finding a reference metric for the rate of biological aging is key to understanding the molecular nature of the aging process. Defining and validating this metric in humans opens the door to a new kind of medicine that will overcome the limitation of current disease definitions, approaching health in a global perspective and bringing life course preventative measures to the center of attention.

Comments

What if a biomarker of aging simply doesn't exist? Maybe it's like trying to find a number that accurately measures the performance of a basketball player or a musician. Simply it doesn't make sense. Or maybe we can find one but it only measures natural aging, and when you apply one rejuvenation therapy, then it become useless. Say, 1000 people have the same epigentic age, then you treat them with the same senolytic and suddenly you obtain a huge variation in their epigenetic ages.

Posted by: Antonio at December 23rd, 2019 4:50 PM

Hi there, just a 2 cents.

''Is biological aging is the cause of the global susceptibility to disease with aging''

Absolutely & Unquestionnably, the answer is in the question/asking it is answering it (with a yes).

''Are there genetic traits that are associated with faster or slower biological aging? Are there "hallmarks" that are better at capturing biological aging at different stages of life?''

Again, absolutely.

Aging and age are measurable, Selonytics on their own I am doubtful will make substantial impact on maximal longevity but on average lifespan yes; the reason is because senolytics act by stopping senescent cell accumulation and SASP from them; it also stops oncogene, but I think it is not enough to stop them (for being 'reactivated' over time); epigenetic regulation is sufficient though (albeit it's not entire story, we have to take account of the damages/DNA DSBs/telomereic foci lesions and other nuclear DNA insults). We see this with strong activation of tumor supressor genes/oncogenes when senescence happens (to try to destroy said senescent cells from mutating into tumor/canceR). Thus, there is ROS formation at that moment, senolytics like quercetin do reduce ROS because they affect these oncogenes (via epigenome switches/remethylation), and in the 8th decade of human life there is Huge Burst of ROS...caused (not just correlation) by the arrival of oncogene to create 'replicative senescence' (of aging/time passed, at 90+ years old it not spontaneous senescence the main problem, it's replicative one because you exhausted all the replicative bouts (which means your telomeres are short and short telomeres = DDR = rep. senescennce oncogene arrival = massive ROS from mitos)). It's why inthe space of a decade or two you can die. I take it that this 'soft limit' was engineered/because your purpose was completed and at 100 years old, your are an outlier int he animal kingdom (as an avanced animal not a simple one like an imm*rtal jellyfish..which uses telomerase/infinite stem/always long telomeres/never run out of telomeric DNA/never empty the epigenome of its methyls/never accumulating continuous lipofuscin/progerin/lamina, their stem germ cell rebuilding of its tissue/continuously 'remorphing' to a Young state/thus not mortal). For now, if therapy can't make/reversion of epigenetic age, I don't see any therapy int he future making lifespan elongation by Much (above maximum 120ish), and also, if we can't do epigenetic age signature reversal then...there is never going to be a lifespan extesion for humans above max. If we solved DNA loss/damagse with age, then it might be feasible but I have a feeling there is 'wrench thrown in the cogwheels', like a riddle on top of another riddle/problem after problem..after another...it is a maze that we are trying to defeat/find exit. Maybe, if somehow, we 'bypass' epigenetic regulation we could 'bypass' normal aging processes and then YES it would be possible to Overcome the Limits imposed of evolution. But, not holding breath, how do you Outwit evolution/millions of years...you (nearly) can't. Yet, in laboratory...miracles are happening, so we must temper hope and pray for a (small) miracle. I am confident to say that lifespan elongation, aging/death - ARE- curable - 100%..and not baloney and not some ludicrous thing. It is the biggest challenge that humanity faces and we must overcome it in the next 5 decades. For people that are older...it'S tough...because all signs put to the fact that if you are older and you are of 'your biological age = chronological age'...it's very unlikely that you will live Beyong 120 Because in several sutdies it was demonstrated that IN order to Live a Very Longe Life..you must Acquire Phenotype Early(ier) Much earlier...meaning it is the Total of lifespan (the events that happened Earlier) that dictates how long you live. Animals that could muster Strong Anitoxidation and Strong protection/detoxification in very Young age and KEPT it for decades..were the Survivors in the decades later. Those that were not there anymore is because there could Not muster enough protection in their early age long ago (thus, for their whole lief, they 'were epi biologically older'...and thus, closer, to their death/hence why tehy do not reach 120). Think of it like the thing that happens with older fathers that give long telomeres to children (because of sperm transfer of long telomeres at conception, older fathers had longer telomeres in spermztozoid DNA, mature sperm had 'time' for telomerase to 'act on it', not young sperm; with taht ssaid, the older it is the more defects will happen but overall, telomeres rises with age in testiucles due to constatnt telomerase in it (this is an evolutive advantage given to men/make babies whole life while women have less of so, have set number of eggs, sperm is renewed)). Thus, if you have longer telomeres at Birth...you have 'more (slack)' to beging with...it is why..children of older fathers can Outlive children from Young father..because they are givin more 'telomere chunk' which decades later - mean Taller Telomeres...by then. SAme thing, with aging, if you could not muster enough protection/telomeres size/antioxidation in your YOUNG age...then it is Very doubtful you will reach old age (as if it will 'change suddenly 'in mid-life'...most likely not; though you can 'slow it down'...not stop your Earlier Lacking). This was shown in clams, the most long lived had mustered the most protection in Young age - and espeically Kept it/maintainted - it for decades, the same. Just look at Jeanne Calment, at 20 and 40...she looked easiler Half her age. IT'S no Wonder why she lived this long, she was much more biologically Younger - Her whole life, so she 'reached farther' down the line/decades later. All this is supposing we can't revert the damages of age and make an old person Reverted to a Young state...because if we can..then it is moot, and aging is defeatable even in Very old/centenarian people (even if they are a 100 years old now). Otherwise..no it is not possible and you will sill die at 120 or less because you will have 'the cumul of your life' in you - which will make you die earlier/or later, but not much later than 120 like everyone else in history (too short telomeres in a115 year old woman in immune leukocyte = immunoscenescence = viral malady/cancer; damages/DNA frags..transthryrein in heart,amyloid, AGEs,ALEs, mitos, p21 replicative hayflick, etc)

Just a 2c.

Posted by: CANanonymity at December 23rd, 2019 10:19 PM

Dear CANanonymity, the eureka in discovering anti-aging is just a matter of time! We are certainly close! Just look at what's happening in Silicon Valley!

Posted by: Gionei at December 29th, 2019 7:02 AM

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