The main reason why we are skeptical about single cause of aging is that there is no single mutations which result in large jumps of life expectancy inside aging species.

Attention would shift to a concrete causal agent.

This is what most translational scientits do. In general, mechanism of action is very important and usefull. On the other hand, a bulk screen of huge compound libriries tries to find a cytotoxic agent (anti-cancer) or pro-survivale molecule without any knolege on mechanism of action. If it works, who cares about mechanism? If I can cure sarcoma, mechanism could be important, but much more important is pharmacology of the drug.

If a molecule extend the life-span several times, I generally would not care about mechanism, unless drug itself just points to it.

The existence of aging master regulators:

The logic is as follows:

1) The molecular aging clock and the master driver of the functional deterioration of any tissue in any organism = mtDNA copy number.

"Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 in skeletal muscle from aged human subjects. "  

https://doi.org/10.1016/S0014-5793(01)02628-X

Aging involves an increase in mtDNA copy number; however, this DNA is not expressed.

There exists a well-documented conflict between mtDNA replication and transcription. “Since replication of mtDNA coincides with transcription in time and space, collisions between transcription and replication machineries are inevitable and, similar to bacterial and eukaryotic systems, likely have detrimental effects on mtDNA gene expression.” Mitochondrial biology. Replication-transcription switch in human mitochondria. Science 347, 548–551.

Replication, apparently incomplete replication, prevails; transcription is supressed, and the cells, tissue, organism die.

2) Substances that inhibit mtDNA replication and promote transcription lead to a substantial extension of lifespan.

In C. elegans, this amounts to an increase in lifespan of approximately +100%, sometimes 150%, sometimes 80%.

3) The same substance protects normal human cells in culture from death within a monolayer (simulating dense tissue) by reducing the mtDNA copy number.

4) Very preliminary data shows that the same drug may work on mice.

Can any disease be cured before we understand its full nature?

Historically, we know examples where the disease, the therapeutic agent for relief, the true cause of the disease, and the final therapeutic agent were discovered with large gaps in time.

Here are the cases I found.

Malaria

The fevers themselves have been known since antiquity. Hippocrates described them in the 4th century BCE. People saw recurring fever, weakness, death, and a connection with swampy areas, but explained it through “bad air.”

Cinchona bark began to be used in Europe around the 1630s. It did not come from an understanding of Plasmodium, the liver, erythrocytes, mosquitoes, or the parasite’s life cycle. It came from observation: people with periodic fever got better after taking the bark.

Quinine was isolated in 1820. Alphonse Laveran saw the malaria parasite in the blood of patients in 1880. The role of mosquitoes was shown by Ronald Ross in 1897, and the transmission of human malaria by Anopheles mosquitoes was confirmed by Italian researchers in 1898–1899.

So malaria was treated with cinchona bark roughly 250 years before the parasite was discovered, and roughly 260 years before mosquito transmission was understood.

But precision matters here. Quinine really did act on the blood stage of the parasite and could save people from an attack, but it was not a complete solution for every form of malaria. Radical cure for many forms required other drugs.

Scurvy

Scurvy has been known since the age of long-distance sea voyages in the 15th–16th centuries, while scurvy-like conditions were described even earlier. A person became weak, the gums bled, old wounds opened, teeth fell out, and death followed.

In 1747, James Lind, knowing nothing about vitamin C or collagen biochemistry, conducted his famous experiment on sailors. He gave different groups different treatments and saw that oranges and lemons worked radically better than the alternatives. He did not know that the human body does not synthesize ascorbic acid, but he saw that citrus fruits brought people back from a condition that often ended in death.

Vitamin C was isolated in 1928 by Albert Szent-Györgyi. Its connection to scurvy was established in the early 1930s, and its chemical structure was finally determined in 1933.

From effective treatment of scurvy with citrus fruits to a proper chemical understanding of the cause, about 190 years passed.

Aspirin

Pain, fever, and inflammation were treated with willow bark even in antiquity. One of the known early European sources of the modern scientific era came in 1763, when Edward Stone reported to the Royal Society on the effect of powdered willow bark in fever.

Salicin was isolated from willow bark in 1828. Salicylic acid was obtained later in the 19th century. Acetylsalicylic acid became the Bayer drug.

The mechanism of aspirin through inhibition of prostaglandin synthesis was explained by John Vane in 1971.

So the drug was used roughly 70 years before its key mechanism was understood. And if we count willow bark, practical use began two centuries before prostaglandins were understood.

But this was not the cure of a disease. It was control over pain, fever, and inflammation. It was not etiological cure, but control over an important pathological pathway.

Lithium

Mania and melancholia were described very early, but the modern framework of manic-depressive illness was shaped by Emil Kraepelin in the 1890s. The term bipolar disorder became an official diagnostic category in DSM-III in 1980.

In 1949, John Cade in Australia was investigating a hypothesis about toxic substances in the urine of manic patients. In the process, he used lithium salts and noticed their calming effect. Then he gave lithium to patients with mania and saw a strong effect.

In 1954, Mogens Schou conducted a controlled trial of lithium in mania. In the United States, lithium was approved for the treatment of mania in 1970.

This was not the result of understanding the nature of bipolar disorder. Again, it was an empirical hit on a powerful regulatory lever.

The mechanism of lithium still cannot be reduced to one simple formula. There are effects on intracellular signaling, GSK-3, inositol metabolism, neuroplasticity, and circadian rhythms. But no one can honestly say that first there was a complete theory of bipolar disorder, and then lithium was rationally derived from it.

The important point is that lithium does not remove the cause of bipolar disorder, but it changes the trajectory of the disease, reduces the risk of episodes, and can sharply reduce the risk of suicide.

Antipsychotics

Schizophrenia was introduced by Eugen Bleuler in 1908 and described in detail by him in 1911. Before that, Kraepelin had described a similar group of conditions in the 1890s as dementia praecox.

Chlorpromazine was synthesized in France in 1950 and began to be used in psychiatry in 1952. It emerged from antihistamine, sedative, and anesthesiology research. Doctors noticed that it reduced psychotic agitation without simple crude narcosis.

After that, psychiatry changed. First came the drug, and only then did theories of dopamine and psychosis begin to form around its action. The dopamine hypothesis of schizophrenia took shape in the 1960s and 1970s.

So the antipsychotic entered clinical use roughly 10–20 years before the mature dopamine theory of psychosis.

This is why the question “can we treat without understanding?” seems a little too crude to me.

Conclusion

The history of medicine does not tell us that, in order to defeat a disease, we must always understand it completely first. But it also does not tell us that it is enough to find a beautiful biomarker and learn how to move it.

A thermometer is very useful. But you cannot cure an infection by optimizing temperature forever.

A problem can be defeated without a complete theory if, by accident or by directed search, a real causal lever is found.

The important question here is whether we have either such a lever or an understanding of how to narrow the search space toward one.

Side note

Cryonics and other critical-care approaches are an answer to the question: “Does the life of the person who will die today matter?” And unfortunately, even solving aging would not solve the problem of irreversible death.

Until one lab working on leproporosis (or lepromentia or any other leprofield) finds in a precise diagnostics that leproporosis might be caused by a bacteria. The end.

So the hard questions remain. Is aging curable in any meaningful sense? Is it even the kind of thing that can be cured? Could a disruptive discovery change the whole field? And if such a discovery is possible, where is it most likely to come from?

In my opinion, aging is a decline in the organism’s viability with age. Each species has its own set of causes, which can be ranked by their degree of influence. Most of these causes are already well known.

The shorter an organism’s natural lifespan, the easier it is to extend its life, and the fewer causes act simultaneously during the last quarter of its average lifespan. In humans, there are thousands of such causes. They accumulate especially strongly after 90–100 years of life, which is why maintaining the organism requires a multitude of therapeutic interventions.

Although most of the causes are known, their sheer number — especially against the background of multiple existing pathologies — makes the therapy of aging practically impossible at present. The only realistic solution here is a radical simplification and replacement of most of the body: transplanting a new body while focusing targeted therapy solely on the brain. This would dramatically reduce the complexity of the task.

In other words, the first real therapy for aging will emerge after whole-body transplantation becomes possible. At that point, the head will be treated with modern methods, while the new body, instead of sending pathological signals, will send rejuvenating ones. This will be the first clear case of victory over aging.

Over time, technologies will be developed that require far fewer replacements. Eventually, we will create a “cocktail” of microrobots — for example, based on hundreds of different CAR-T cells — capable of treating the entire organism. At the same time, it will still be necessary to perform numerous genetic modifications to improve the phenotype both in already living people and in future generations. The goal is to slow down the rate of aging, activate regeneration processes, and enable rejuvenation.

In my worldview, we basically understand the cause of aging. The deep cause is physical.

We live in an oxygen-rich atmosphere. Oxygen oxidizes molecules. Molecules break. Proteins misfold. DNA is damaged. Cells drift away from their original state. A living organism is not a stable object. It is an unstable, self-repairing system that survives only because it constantly renews itself.

This is why I really like the latest papers of Ben Shenhar and Peter Fedichev: aging can be viewed as the balance between damage accumulation and damage recovery. At some point, damage recovery cannot keep up. That limit is what shapes maximum lifespan.

So in that sense, the root cause cannot simply be “removed.” The cause is not one bacterium, one pathway, one toxin, or one evolutionary mistake. The cause is oxygen in the atmosphere, thermodynamics, and the fact that we are made of unstable molecules. Of course, one can freeze oneself, but that is not solving the problem.

This is the important distinction: the underlying cause of damage accumulation is external to life. It is not a property of life itself. In fact, a living system is alive precisely because it is fighting this external pressure. Life is not aging because it wants to age. Life is aging because it is constantly resisting decay, and eventually failing.

But why then do living systems fail to resist degradation forever?

This is where plaques may enter the picture. They definitely shape maximum lifespan. They create pressure. They may prevent the evolution of cleaner, longer-lived, better-maintained organisms. But they are still secondary.

You can imagine an organism with no plaques at all, and it would still age. You can remove every obvious external disease factor, and oxygen would still be there. Molecular instability would still be there. Damage would still accumulate.

Hydra avoids aging by making every cell replaceable. In principle, if humans could replace every cell in the body with a fresh version, we would not age at all.

So why does that not happen?

The answer is probably not that nature “could not” do it in some abstract sense. We can imagine breeding species (humans) for millions of years toward longer and longer lifespans. Maybe, eventually, a mechanism could evolve that replaces every cell, every structure, every damaged component, while preserving the organism’s identity and function.

But humans did not evolve that.

Why? Because we are too complicated. Because replacing every cell in a tiny simple organism is one thing, and replacing every cell in a brain, immune system, vasculature, endocrine system, reproductive system, and memory-bearing organism is another. Because evolution optimizes under constraints. Because selection weakens after reproduction. Because pathogen pressure, plaques, infections, and many other forces may have made such a strategy too costly or too unlikely to evolve.

This is where the plaque hypothesis might matter. It may explain why some long-term maintenance mechanisms never evolved.

But it does not solve the central problem.

Even if we removed all plaques completely today, we would still not suddenly have a body-wide mechanism for perfect renewal. We would still not have a natural way to replace every old cell, every damaged structure, every drifted molecular state with a fresh one. We would still need to fight oxygen, entropy, instability, and accumulated damage.