Notes about Fedichev et al. minimal aging model paper

Already in the introduction I find a part that I think is, let's say, problematic:

Within this framework, aging is defined as the cou- pled evolution of dynamic stress-response variables (z0 ) and the slow, largely irreversible accumulation of en- tropic damage (Z), modulated by intrinsic and extrin- sic stochastic fluctuations (D0 ). This perspective con- strains the achievable effect sizes of interventions. Ther- apies that act only on dynamic, age-dependent fac- tors—corresponding to many of the established hall- marks of aging—are inherently limited in stable species such as humans, where resilience loss is driven primar- ily by damage accumulation. Larger and more durable gains would require reducing physiological noise or, more ambitiously, slowing the accumulation of damage itself, the latter offering the only route to shifting maximum lifespan.

This entire premise seems problematic: what this implies (in my understanding) is that the "ideal" approach to fixing aging would be full cellular reprogramming such that the body does not at all incur aging / increase entropy any longer. And as a result the accumulation of entropic damage Z would not rise any more.

While this is clearly the optimal approach that will result in "perfect immortality" it seems bizarre to focus on so much.

The time scales at which damage accumulates in humans is decades. As a result, if we had interventions which just fix damage / get rid of garbage we'd reach effective LEV already, despite the fact that our increase in entropic damage per time would be the same as now. But that's a perfectly fine solution in my book.

Whether, when looking back from a 100 years in the future, it turned out to be easier to just do the reprogramming to "fix our biology" or just fixing the accumulation of damage is of course a valid question. It seems to me though that fixing stuff is inherently easier than rewriting biology such that these problems don't occur in the first place.

In particular the last sentence:

the latter offering the only route to shifting maximum lifespan.

implies to me that we would be talking about shifting maximum lifespan without further interventions, which is a crazy ambitious goal.

In particular I have one issue with this statement:

A rewrite of our biology is surely a superset of more standard interventions aimed at "local" entropy reversing approaches (i.e. fixing DNA damage, killing senescent cells, …). If one can rewrite our biology not to accumulate damage in the first place, it seems like doing the more "standard" cellular reprogramming approaches are already viable.

Note that later in the paper when they introduce the 3 different levels of interventions, in level 3 they have:

Nonetheless, several conceptual avenues exist: molecu- lar repair technologies, clearance of irreversibly damaged cells or macromolecules, organelle replacement, genome and epigenome editing, or large-scale cell and organ replacement therapies. The most ambitious strategies would ultimately aim to arrest the linear growth of Z altogether—an achievement that would not only extend lifespan but also fundamentally reshape the trajectory of functional decline, shifting the maximum lifespan itself.

Here they clearly include the kind of solutions that most people in the field would expect to be the "correct" ways to fix aging as those that "shift the maximum lifespan itself". That seems somewhat in contradiction to the section I quoted above, which made it sound like only direct reduction in entropy accumulation would be a real solution.

I'm confused.

They mention the following:

In stark contrast, engineered systems typically fail with power-law hazards rather than exponential ones [30–32]. That biology so consistently produces Gompertzian dynamics suggests a form of universality in aging that is absent from non-biological failure modes.

This seems to make sense, because engineered systems don't have repair mechanisms. Those would (intuitively) be the reason for the difference.

One slightly more critical issue of the paper to me is that it never defines the potentials it talks about, i.e. fig. 1a) (\(U^\text{act}_i\)) and 1c).

It only defines the equation of motion for \(\dot{z}_0\). While one can derive a potential that satisfies this from the given equation of motion (maybe we would make some assumption about Langevin dynamics, which the paper's model is based on, not sure), but still it would be nice to have the equations for the potentials explicitly.

In sec. VI they say the following:

If Z reflects configurational entropy, its linear growth represents a direct manifestation of the second law of thermodynamics—an irreversible increase in entropy over time. This perspective clarifies why reversing accumulated damage is so difficult: it would require restoring an astronomical number of microscopic degrees of freedom to their initial, highly improbable configurations.

and then in sec. VII, level 3 they write:

Because Z reflects configurational entropy, it is unlikely to be reversed by current technologies.

In the first statement we are still clearly talking about an assumption, whereas in the second we then pretend that assumption is actually proven. I'd argue that if anything, Z corresponds to a practical equivalence (at the coarseness at which we look at biology with this model). If the Z does not actually correspond to entropy as understood in thermodynamics, then it is wrong to conclude that reversing aging is going to be – effectively – impossible, as this states.

The reason why in my opinion it may not make sense to map Z explicitly to real entropy is that the model assumes we are dealing with a system made up of a huge number of independent subsystems that evolve independently. It seems much more likely (and biologically motivated based on chemical signaling etc.) that a biological system is in fact made up of a large number of highly interconnected or correlated subsystems.

As a result, it may be reasonable to assume that an intervention targeting one subsystem that interacts with other subsystems could have an effect vastly beyond what the minimal model of the paper would suggest. E.g. how the inverse happens, i.e. senescent cells and SASP. It seems lie they are an example of where one subsystem going crazy can drastically change the noise in a local region around the system in a negative way.

In section VIII they mention:

Our framework extends the classical Strehler–Mildvan (SM) theory [93] by mapping the SM concept of a “vitality deficit” onto the cumulative damage Z, identifying z0 as the reaction coordinate underlying Gompertzian mortality, and assigning D0 a temperature-like role – all identifiable from molecular level data. In this way, parameters that were purely empirical in the original SM theory acquire clear physical and biological meaning.

I'm not sure how accurate it is to say that the parameters acquire a "clear physical and biological meaning". It seems more accurate to say that we have a relation to parameters used in physics. But clearly it is not trivial to say what the "temperature-like role" actually means in practice.

"clear … meaning" to me would imply that we wouldn't have a problem to directly go ahead and measure these parameters in an individual (or at least describe a setup of how one could do that theoretically). At this point I don't quite see how one would even do that conceptually, because to me at least, the relation of the parameters to the biological systems is still a bit nebulous.