Something is going to get you in the end — it could be cancer, diabetes, or a lightning strike. But what if, in a perfect world, you were able to avoid all of those calamities, do away with the everyday stressors that compound to chip away at your health, and truly die of "old age"?

Numerous studies have investigated this question before, and much of our current understanding of the complex relationship between aging and the changes in physiological variables have come from large cross-sectional studies and led to the increasing accuracy of so-called "biological clocks" that base human longevity factors on blood markers, DNA, and patterns of locomotor activity.

Of course, many of the hallmarks of aging - stem cell exhaustion, altered intercellular communication, epigenetic alterations, and genomic instability - can be addressed pharmacologically. But if you truly want to live longer, it takes more than drugs and therapies, because the recovery rate from those hallmarks of aging must also be addressed.

In May 2021, a research team at Gero, a biotech company based in Singapore, who worked in collaboration with the Roswell Park Comprehensive Cancer Center in Buffalo, New York, presented the results of a study of the associations between aging and the loss of the ability to recover from those everyday stressors.

The findings of the research included an estimation of how long a human might live if everything went off without a hitch, and they might surprise you.

How Long Can You Live? That Answer Depends on ‘Resilience’

In the study, which was published in the journal Nature Communications, Gero researcher Timothy Pyrkov and colleagues looked at the "pace of aging" in a large collection of people from the U.S., U.K., and Russia. They evaluated deviations in stable health by assessing changes in blood cell counts and the daily number of steps taken, then analyzed those by age group.

For both the blood cells and step counts, researchers found that the pattern was the same: as age increased, a factor not associated with a disease created a predictable decline in the body’s ability to return blood cells or gait to a stable level after a disruption. Pyrkov and colleagues then charted that incremental decline out to the point where resilience disappeared completely, and took that as the age at which death would occur.

The result?

"Extrapolation of this trend suggested that dynamic organism state indicator (DOSI) recovery time and variance would simultaneously diverge at a critical point of 120-150 years of age corresponding to a complete loss of resilience," the authors wrote, adding that the observation was confirmed by an independent analysis of correlation properties of intraday physical activity level fluctuations that were collected by wearable devices.

It is important to note that the researchers’ correlation was key to the finding. Measurements such as blood cell counts and blood pressure have a known healthy range, while step counts are unique to each person. The fact that steps and blood counts showed the same decline over time makes them a real pace-of-aging tool.

What the Loss of Resilience Means for Maximum Lifespans

Social factors backed up the study’s findings as well. Recovery times for a 40 year old are around 2 weeks, but that stretches to 6 weeks for an 80 year old. The predicted loss of resilience, even among those who are the healthiest, could explain why there will not be an eventual increase in this maximum lifespan, even though average lifespans are steadily increasing (or at least they were up until the mass mortality numbers created by COVID-19).

This also means that any intervention that does not affect the decline in resilience will also not effectively increase the maximum lifespan - instead, we would only see an incremental increase in human longevity.

"Accordingly, no strong life extension is possible by preventing or curing diseases without interception of the aging process, the root cause of the underlying loss of resilience," noted a press release detailing the study. "We do not foresee any laws of nature prohibiting such an intervention. Therefore, the aging model presented in this work may guide the development of life-extending therapies with the strongest possible effects on health span".

A New Look on How We Age

The study’s author presented a schematic diagram of their interpretation of how humans age, with age mapped against dynamic organism state indicators as a flowing line bumping between regeneration and injury or illness, with the deviations between the two growing as a human loses the ability to recover from shock and stress.

"Far from the critical point (at younger ages), the organism state perturbations can be thought of as confined to the vicinity of a possible stable equilibrium state in a potential energy basin," they wrote in the study. "Initially, the dynamic stability is provided by a sufficiently high potential energy barrier separating this stability basin from the inevitably present dynamically unstable regions in the space of physiological parameters. A health span state experiences stochastic deviation from the metastable equilibrium state, which is gradually displaced in the course of aging even for the successfully aging individuals".

In the presence of a stress, they explained, the loss of resilience leads to destabilization of the body’s health state. When protective barriers are crossed, stability is lost, "and deviations in the physiological parameters develop beyond control, leading to multiple morbidities, and, eventually, death. The end of health span can therefore be viewed as a form of a nucleation transition, corresponding in our case to the spontaneous formation of states of chronic diseases out of the metastable phase (healthy organisms)".

So what do the authors propose can be done to simply live longer? They point to therapies that would target frailty-associated phenotypes such as inflammation. In those who are frail, such an intervention would produce lasting effects and reduce frailty, which would increase lifespan beyond health span.

References:

1. Levine, M. E. Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age? J. Gerontol. A Biol. Sci. Med. Sci. 68, 667–674 (2013).

2. Aleksandr, Z. et al. Identification of 12 genetic loci associated with human healthspan. Commun. Biol. 2, 1–11 (2019).

3. Mitnitski, A. & Rockwood, K. The rate of aging: the rate of deficit accumulation does not change over the adult life span. Biogerontology 17, 199–204 (2016).

4. Sudlow, C. et al. Uk biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).

5. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).

6. Gijzel, S. M. W. et al. Resilience in clinical care: getting a grip on the recovery potential of older adults. J. Am. Geriatr. Soc. 67, 2650–2657 (2019).

7. Lippi, G., Salvagno, G. L. & Guidi, G. C. Red blood cell distribution width is significantly associated with aging and gender. Clin. Chem. Labor. Med. (CCLM) 52, e197–e199 (2014).

8. Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10, 573 (2018).

9. Avchaciov, K. et al. Identification of a blood test-based biomarker of aging through deep learning of aging trajectories in large phenotypic datasets of mice. Preprint at bioRxiv https://doi.org/10.1101/2020.01.23.917286 (2020).

10. Pyrkov, T.V. & Fedichev, P.O. Biological age is a universal marker of aging, stress, and frailty. In Biomarkers of Human Aging, 23–36 (Springer, 2019).

11. Belsky, D. W. et al. Quantification of biological aging in young adults. Proc. Natl Acad. Sci. 112, E4104–E4110 (2015).

12. Sara, A. Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nat. Med. 26, 83–90 (2020).