What is aging? Sadly, we don’t know. If we ask the experts in the field, they will give us different answers [1]. Consensus has not been reached on even the trivial definition of aging, let alone its primary mechanisms. But, can we cure aging without understanding it? I think not. Knowledge is essential to target the fundamental causes of a disease; otherwise, we risk focusing on its symptoms.
Why is a paradigm important?
Let’s do a thought experiment: try curing COVID-19 without knowing it is caused by a virus. We may attempt to reduce the patient’s temperature, headache, nausea, and cough, which will help a little. Encouraged by this minor progress, we will keep improving our remedies and likely stay busy forever, without any major results. Moreover, we can easily construct twelve “hallmarks of COVID” without having any idea about infection and try to use this “paradigm” to develop further treatments. Would AI-driven analysis of multi-omics datasets suggest the ultimate cure for COVID-19, vaccination, if it could not identify the virus under the conditions of our thought experiment? Also no.
How can we come up with the idea of vaccination? Only with a fundamental scientific model of infectious diseases and immunity. One can replace COVID-19 with any autoimmune or genetic disorder and see that, in most cases, a basic understanding of the underlying process is essential for identifying mechanisms and developing a cure. Why should aging be different?
This is why I believe our journey toward curing aging has not even truly begun and will not begin until we find out what aging is, or, in other words, build a scientific paradigm. How can such a paradigm be built?
Building the paradigm
Most researchers attempt to explain aging via its cellular and molecular mechanisms. However, biological systems are incredibly complex, and there are so many degrees of freedom that it is possible to build an internally non-contradictory aging model around virtually any biological process or random gene in the genome. Testing such models is not trivial: for example, disproving Harman’s oxidative theory of aging took several decades. Do we have time to test hundreds of other mechanistic models?
A better approach would be to prioritize understanding aging as an ecological phenomenon. Aging has evolved for a reason, and since “nothing in biology makes sense except in the light of evolution,” this approach is more stringent, allowing us to discard incorrect theories. Only a handful of models attempt to explain the evolution of aging. We in our team believe all of them are flawed; their assumptions are unrealistic, and nobody has found evolutionarily stable pleiotropic genes or the fundamental physiological trade-offs on which these theories rely. Also, the basic predictions of these models do not hold. Moreover, they cannot explain puzzling ecological observations such as the correlation between longevity and flight, extreme longevity in naked mole rats, or huge differences in lifespan between castes of eusocial insects [2, 3].
In our lab, we are developing an alternative evolutionary model that may become a new scientific paradigm for aging and pave the way to curing it.
The two types of models
The crucial point is the choice between damage-centered and program-centered models. Is aging an accumulation of entropic damage or a genetic program that kills us? These two alternatives are mutually exclusive, and choosing the correct one is key for designing strategies for anti-aging interventions.
If aging is the accumulation of damage, we need to fix this damage. If aging is a genetic program, we need to localize it in our genome and switch it off. In the first case, we fix something; in the second, we break something. These are two fundamentally different projects, and if we make the wrong choice, we risk wasting all the time and resources invested.
Currently, most scientists consider aging a damage accumulation process. However, no experiments proving that aging results from damage exist. Programmatic models can rationalize all the experiments and observations made so far. Why, then, are scientists so confident that aging is not a program? Because they have strong reasons to believe it cannot be one.
There are two seasoned arguments against programmed aging:
- It is not clear what evolutionary purpose programmed aging could serve.
- If aging is a genetic program, there should be genes that execute it. Mutations in these genes should make animals non-aging, but we do not observe such mutants.
Pathogen control hypothesis
To make a long story short, we have constructed a model that overcomes these arguments and supports the view of programmed aging as an evolutionary adaptation [4].
First, what is aging good for? Imagine an epidemic of infectious disease in a population of animals. This disease does not kill, but it cannot be removed by the immune system, resulting in chronic infection. It still damages the organism, impairing its ability to reproduce. Examples of such chronic sterilizing diseases in humans include gonorrhea, syphilis, genital herpes, and other sexually transmitted disorders. An animal infected with such a disease is useless for evolution; it cannot reproduce. Moreover, it can infect relatives who live nearby, potentially harming the propagation of its own genes.
In such cases, removing infected individuals may become evolutionarily advantageous. The probability of being infected with a chronic disease increases with age. Therefore, after a certain age, most individuals are expected to be infected and thus detrimental to the dissemination of their own genes. Evolution may have developed mechanisms to remove such individuals, using age as a proxy for infection risk. In this view, aging may have evolved as a primitive but universal immune mechanism, protecting kin from chronic infections that accumulate with age.
Second, why are non-aging mutants so rare? Such mutants must exist in principle: negligibly aging naked mole rats share common ancestors with other rodents. Thus, at some point during evolution, an aging mother must have produced a nearly immortal pup. Yet, for some reason, aging is extremely stable, and such cases are very rare.
Why might this be? Let’s look at species where aging is less stable: eusocial insects. Queens in ants, bees, and termites live far longer than workers, suggesting that the aging program is plastic in these species. Surprisingly, some parasites allow infected workers to age at the queens’ pace, almost fifty times slower [5]. Why do parasites do this? Because they benefit from their hosts living longer and continuing to disseminate the parasite’s progeny.
If aging evolved as a disease control mechanism, pathogens may have evolved ways to inhibit it. In response, hosts may have developed “security harnesses” that prevent manipulation of aging by pathogens. These might involve coupling aging to vital functions that would be damaged if aging were switched off. As a result, inhibiting aging, whether by pathogens, mutations, or pharmaceuticals, might harm or even kill the organism. These evolutionary stabilizers can explain the rarity of non-aging mutants.
Thus, the pathogen control hypothesis overcomes the classic arguments against programmed, adaptive aging, removing key reasons to believe that damage is the primary cause of aging.
Unlike other models, the pathogen control hypothesis relies on realistic and straightforward assumptions: the existence of chronic sterilizing epidemics and population viscosity. It also explains puzzling phenotypes not accounted for by damage-based models, such as the correlation between longevity and flight, slow aging in naked mole rats, semelparity, and caste-specific lifespans in eusocial insects [2].
By conventional epistemological criteria, pathogen control should be considered a leading candidate among models of aging.
Practical takeaways
If this model is correct, what consequences does it have for the field?
The pathogen control hypothesis proposes that aging is a functional part of immunity. Therefore, immune aspects should become a central focus of longevity research. In line with recent discoveries [6], aging may involve a gain-of-function mechanism, where aged immune cells damage tissues.
If the pathogen control hypothesis is correct, rejuvenating the immune system should be the first and most immediate priority in our quest to defeat aging and death.
Literature
[1] Gladyshev VN, Anderson B, Barlit H, Barré B, Beck S, Behrouz B, Belsky DW, Chaix A, Chamoli M, Chen BH. Disagreement on foundational principles of biological aging. PNAS nexus. 2024;3(12):pgae499.
[2] Lidsky PV, Yuan J, Rulison JM, Andino-Pavlovsky R. Is aging an inevitable characteristic of organic life or an evolutionary adaptation? Biochemistry (Moscow). 2022;87(12):1413-45.
[3] Lidsky PV, Andino R. Could aging evolve as a pathogen control strategy? Trends in Ecology & Evolution. 2022;37(12):1046-57.
[4] Lidsky PV, Andino R. Epidemics as an adaptive driving force determining lifespan setpoints. Proceedings of the National Academy of Sciences. 2020;117(30):17937-48.
[5] Beros S, Lenhart A, Scharf I, Negroni MA, Menzel F, Foitzik S. Extreme lifespan extension in tapeworm-infected ant workers. Royal Society Open Science. 2021;8(5):202118.
[6] Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, Cui Y, Angelini L, Lee K-A, McGowan SJ, Burrack AL, Wang D, Dong Q, Lu A, Sano T, O’Kelly RD, McGuckian CA, Kato JI, Bank MP, Wade EA, Pillai SPS, Klug J, Ladiges WC, Burd CE, Lewis SE, LaRusso NF, Vo NV, Wang Y, Kelley EE, Huard J, Stromnes IM, Robbins PD, Niedernhofer LJ. An aged immune system drives senescence and ageing of solid organs. Nature. 2021;594(7861):100-5. doi: 10.1038/s41586-021-03547-7.
