Whole-body approach to age reversal

NickOttens

The feedback of experts in- and outside the XPRIZE Community, as well as our sponsors, has convinced us to move away from a focus on the immune system toward a whole-body approach to age reversal.

The winning team in this competition would demonstrate an intervention that rejuvenates several systems of the human body and reduces epigenetic age by X years (TBD).

Four systems are especially susceptible to aging:

1. Cardiovascular system
2. Immune system
3. Central nervous system
4. Musculoskeletal system

We would stipulate 3-4 relevant biomarkers for each system. Competitors would need to demonstrate a positive effect on X biomarkers in X categories to win, and reduce epigenetic age.

Our questions for you:

• How many biomarkers per system would suffice?
• Should competitors demonstrate age reversal in all four systems of the body?
• Should rejuvenation of each system be weighted the same?
• How many years of epigenetic age reversal can we (safely) ask for?

NickOttens

@Toby_Chronomics, @DidierC, @SamLeTardif, @OnDigitalHealth, @SWBT, @Liz_Parrish, @bjcooper, do you have thoughts on some of our questions related to a whole-body approach to age reversal?

MFossel

Nick:
Your emphasis on a whole-body approach is a good choice, as are your four major systems, although I would prioritize them based on mortality and morbidity, placing cardiovascular first and CNS second, with immune and musculoskeletal systems afterwards. I'd be tempted to add the renal system with particular attention to podocytes, again given the impact upon mortality and morbidity. As for biomarkers, I would again focus upon clinically relevant biomarkers in each case, regardless of the number of markers chosen. The weighting should again -- both within and between systems -- reflect the clinical relevance as measured by mortality and morbidity. As for the number of years, I suggest a clear decade of age-reversal is both feasible and significant.

Michael Fossel, MD, PhD

MariaEntraigues

Happy to see this. I personally will inevitably have to point you out to our Strategies for Engineered Negligible Senescence (SENS). So far there's no other roadmap to addressing aging as a whole and to me there's no better reference than this to understanding aging well and how to tackle it systemically.
You can read about the 7 processes and strategies here: https://www.sens.org/our-research/intro-to-sens-research/

Regarding your questions, I feel like if we could show the audience that we can rejuvenate one system in a human (or even less than a whole system) using a damage-repair approach, that should be compelling enough to get more support and start changing people's mindset about addressing aging as a medical problem in its entirety.

MFossel

To the contrary, since inception, the SENS approach has continued to use a flawed "component" approach to aging, without any attention to a fundamental systems understanding of the underlying pathology. The result has been to focus on 7 components, much like believing that any disease is no more than the sum of its symptoms. This has never been true of medicine or science and is not true of any attempt to comprehend aging. Aging is not merely components (or "biomarkers"), but is systems process that has already been described well in, for example, "Cells, Aging, and Human Disease" (Oxford University Press, 2004) and more recently in "A Unified Model of Dementias and Age-Related Neurodegeneration" in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, January 2020. Moreover, the latter approach has already been used successfully to reverse aging in human cells, human tissues, and (within limits) mice. Until we take a systems approach to aging, we will fail to either understand or intervene successfully in either age-related disease or aging itself. Once we do take a systems approach, intervention becomes feasible if still technically demanding.

Michael Fossel, MD, PhD

nicolas_cher

I'm very happy that, now, it will be aging as a whole, and not just aging in the immune system, which will be the focus of XPrize. Regarding your idea about taking in account both epigenetic rejuvenation and a series of markers in several subsystems, it's tempting and interesting, but maybe it would be simpler and more practical to take in account only the epigenetic rejuvenation, but then, to take a bolder approach — I mean, if the criteria were only the epigenetic age, the bar could be set at 20 years (20 years of epigenetic rejuvenation). I know that taking into account only the epigenetic rejuvenation implies the theoretical possibility that the epigenetic could be rejuvenated in a way that the phenotype isn't rejuvenated, but it's possible that that risk (which is relatively small) is compensated by the clarity of the proposal (20 years of epigenetic rejuvenation).

NickOttens

Thank you for all your comments and advice!

@nicolas_cher, that's something we considered. The question is if more than, say, 10 years of epigenetic age reversal can be achieved safely? From what I understand, we simply don't know, so it might not be wise to set that as a goal. Hence the combination of X number of years of epigenetic age reversal combined with a demonstrated rejuvenation effect on various biomarkers.

@Umbertog, @gatzmon, @YuriDeigin, @efoehr, I'd love to read your thoughts on this as well. Please let us know what you think!

nicolas_cher

@NickOttens , if safety is a concern in the case of a minimum of 20 years of epigenetic rejuvenation, the "safety" itself should be another criterion. I mean, the prize could stablished that the winner should achieve the 20 years of epigenetic rejuvenation in a way proved safe.

MFossel

At Telocyte, we have chosen three primary goals: safety, efficacy, and credibility. We believe that we can achieve all three -- with care, forethought, and attention to technical rigor. The most important prerequisite is the need for a unified systems model that accurately corresponds to physiology and clinical pathology, is consistent with all data, is predictively valid, and offers a technically feasible point of optimal intervention.

goya

I want to share some personal views with the audience. I fully agree with the decision of choosing whole body rejuvenation as a goal for the prize. Indeed, it does not make biological sense to think of rejuvenating a single system that should function in the context of and old body. In higher biological systems like mammals, everything is connected with everything else and the whole body is under the control of a hierarchical network where the central controller is the central nervous system (CNS). Evolutionarily, the purpose of the CNS is controlling and functionally integrating the other (peripheral) systems which in turn feedback on the CNS and, perhaps to a lesser extent, among each other. In my opinion this hierarchical control applies to the epigenetic clock in the same way it applies to circadian clocks and the homeostatic network. We have recently proposed this idea (A hierarchical model for the control of epigenetic aging in mammals, PMID: 3273945).
Most likely, in vivo rejuvenation will be achieved first in animal models. There are some initial results in rodents. In a study with a plasma fraction from young rats, a marked set back of DNAm age was achieved in old rats which was associated to partial rejuvenation of the animals (doi: https://doi.org/10.1101/2020.05.07.082917). Although it is difficult to draw firm conclusions from the scanty results available, it seems to me possible that significantly setting back epigenetic age may not necessarily rejuvenate the phenotype to the same extent. After all, the epigenetic clock is only part of the epigenome.