Wary of the Beautiful Fairy Tale of Near Term Rejuvenation

One might compare this interview with researcher Leonid Peshkin to last year's discussion with Vadim Gladyshev. There is a spectrum of caution and pessimism regarding near term progress towards rejuvenation; the pessimists in the research and development communities are not all alike in their viewpoints, and nor do they all have the same take on the complexity of cellular metabolism as a hurdle to progress.

If a researcher thinks that small molecule drugs or gene therapies to alter the operation of metabolism into a state in which aging is slowed are the only way forward, then yes, it is reasonable to consider that progress will be slow and incremental. Metabolism is far from fully mapped, and thus the detailed progression of aging is also full of unknowns. Yet why take the hard path when there is an easier way forward? The whole point of the SENS approach to aging, based upon repair of root cause damage, is to bypass this complexity and lack of knowledge. Remove the known and well-catalogued damage at the root of aging, and a sizable fraction of the consequences will be repaired by the normal processes of tissue maintenance; we know this because we have the example of youthful individuals and their metabolism to draw on.

Of course, it is then possible to debate whether or not the short-term repair projects that can be achieved in the next ten to twenty years will produce large enough gains in life expectancy to enable people to live to see success in the long-term, harder repair projects. Senolytics, breaking of glucosepane cross-links, clearance of protein aggregates, cell replacement therapies, and more, will all be going concerns in the 2020s. But projects such as repair of stochastic mutations in nuclear DNA or damaged nuclear pore molecules in long-lived and critical populations of neurons are well beyond present capabilities.

An Interview with Dr. Leonid Peshkin

As a way of introduction, I'd like to offer a caricature of the currently popular sensationalist view in the field of aging: "We are the chosen generation. Singularity is near. Rejuvenation therapy is almost here. Not one, several a-la-carte: stem cells, factors from young blood, senolytics, Skulachev's ions, NAD, etc. Companies backed up by luminaries from business and science are already sorting out the remaining details, helped by the formidable force of AI technology called 'deep learning'." This fairy tale is beautiful, and deep in my heart, I hope I am mistaken, but I think that at the moment, this positive mysticism is not justified and is rather counterproductive. The excessive optimism is, unfortunately, standing in the way of progress, as I will try to explain.

There are many proposed models of aging, such as the Hallmarks of Aging, SENS, and the deleteriome. Which, if any, of these models do you believe reflects the reality of aging?

I would not want to take part in religious wars. People get very passionate and clash about often vaguely defined terms. Which of the observed hallmarks of aging, from the molecular to the organism levels, are correlates and which are causes of aging is hard to say. Biology has not yet matured to become an exact science. Perhaps owing to my training in quantitative science I take a "model" to mean a level of quantitative understanding that allows for "modeling"; that is, forecasting and answering "what if" questions. Such a model might not be ultimately expressed by a set of crisp human-readable mathematical formulae but rather a large set of tuned parameters in an artificial neural net or some other representation that has not yet been invented. It must, however, provide a way to assess the current state of an organism and predict its lifespan and healthspan in a stable environment, outside of a major perturbation, and then go further to allow for perturbations and adjust the predictions.

Today, I can't even say that there is an agreement in the field of what is a useful definition of "aging". I like "increase of hazard rate (i.e. the probability of dying) with time", which is admittedly a very mathematical notion - precise and not terribly useful. Inverting this formula, we get a curious metaphor - a life without aging can be imagined as a life where, say, once a year, you undergo a treatment that rejuvenates you a year in biological age, or, with some small but non-negligible probability, kills you. Life is a game of chance.

Do you believe that aging is a one-way process or something that is flexible and amenable to intervention?

It is both. Imagine one dramatic intervention: one day, we invent a way to cryo-protect a warm-blooded organism like ours so that it can undergo a freeze-thaw cycle without damage. Now, you are faced with a challenge to design a schedule that determines when, and in what size fractions, you'd like to use up your lifespan. While you are frozen, time stops. While you are alive, you age: the "deleteriome" kicks in, ionizing radiation wrecks your DNA, your defrosted friends and family du jour stress you out, etc. That's what things would look like ad absurdum, illustrating the tradeoffs.

Now, back to the interventions: I imagine a process not unlike a beauty salon, in which you do your nails and hair and get an occasional facelift; all of these are tradeoffs, even if people do not recognize it. Beauty treatments make you look younger at the moment, but cosmetics products may poison your skin and accelerate actual aging. There is evidence of such tradeoffs across organisms in nature; extending lifespan in many species can be accomplished at the expense of reproduction, and in cold-blooded organisms, you can multiply the lifespan several-fold by just cooling the environment down or slowing down metabolic processes in other ways. I believe that the first results will be not so much in giving people free tickets to longer lives but in making the tradeoffs more explicit, educating people and putting them in control of decision making.

Do you consider epigenetic alterations as a cause of aging or a downstream consequence?

Neither cause nor downstream. There is no linear causal chain with the two links of "aging" and "epigenetic alterations"; instead, there are loops and amplifiers in the circuits of aging. Epigenetic alterations have to be caused by something else; these, in turn, control many things. On the other hand, DNA damage is clearly pretty early in the causal network but is hard to undo. There is more hope to proofread and fix "epigenetic alterations". I am very much interested in this direction of research, so much so that we are planning an experiment looking at changes in the distributions of cell types in cell populations that make up young and old individuals. The expectation is that epigenetic alterations lead to de-differentiation and mis-differentiation of cells in old organisms, which could be characterized and further used as end-points for aging interventions.

Comments

Skepticals are good. Skepticals are needed. Skepticals point out new and relevant problems that will need to be solved.

Posted by: space_cowboy at January 10th, 2019 4:37 PM

Skepticism without enough knowledge or reasoning is useless. He seems to put all treatments and theories in the same bag. As Henri Poincaré once said: "to doubt everything or to believe everything are two equally convenient solutions; both dispense with the necessity of reflection."

Posted by: Antonio at January 11th, 2019 4:05 AM

@Reason, how is the breaking of glucosepane going? Any news? Thanks!

Posted by: Josep at January 11th, 2019 3:53 PM

@Josep I hope they find something soon, it would be even better if they found something that broke glucosepane that was readily available like they found with fisetin destroying senescent cells

Posted by: scott emptage at January 11th, 2019 4:20 PM

@Josep: Quietly. I don't imagine there will be any public disclosure until things are fairly advanced.

Posted by: Reason at January 12th, 2019 12:35 AM

@Ariel: "This is the first demonstration that glucosepane can be broken down enzymatically". Wow!! These are good news! @Ariel, why do you say that they aren't sure enough to make it public? Who are "they" ? Thanks!

Posted by: Josep at January 13th, 2019 3:57 PM

@Josep, they are Spiegel group -- spiegellab.yale.edu

Posted by: Ariel at January 14th, 2019 8:07 AM

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