Biochemistry (Moscow), Home of Programmed Aging
One of the most important divides in the aging research community today is that between the view of aging as a result of the stochastic accumulation of cellular and molecular damage and the view of aging as resulting from an evolved genetic program. The former is the majority position, but the programmed aging camp is fairly vocal these days. Personally, I fall into the aging as damage camp based on my understanding of the literature. The programmed aging view is certainly interesting, but I think its proponents have a steeper hill to climb when it comes to proving their theories.
Why is this an important difference of opinions? It is important because the types of therapy that work well in the world where aging is damage are not so good in a world in which aging is programmed, and vice versa. We are already in a situation in which all too much of the funding for longevity science goes towards research programs that are only capable of producing expensive, marginal outcomes: drug development aimed at slowing aging that attracts funding because it can be sold as a slight evolution of the present methodology of medical research and development. That it can't possibly lead to rejuvenation or indeed any significant result soon doesn't matter: people get funded, and researchers for better or worse chase the funding that can be obtained, not the funding that might be obtained in a better world.
(To my eye it is up to advocates to change the funding landscape: researchers don't tend to try anywhere near aggressively enough. It requires someone from outside the system of patronage and relationships to come in and kick people until they start doing what they should and what is sensible).
But back to programmed aging. This situation, a focus on drug development aimed at slowing aging, or patching over the consequences of damage by altering specific protein levels to resemble the youthful amounts, will only get worse if the programmed aging camp successfully increases their influence in funding circles. To the programmed aging viewpoint the entire problem is that protein levels are wrong, and aging can be reversed by reverting them - reprogramming the machinery. From the aging as damage viewpoint this is the cart before the horse, an approach doomed to expensive failure because it doesn't fix the underlying cause of aging, which is to say the damage itself.
The way to short circuit this slowly ongoing cultural and scientific debate is for a proposed methodology of rejuvenation through damage repair - such as SENS - to be implemented in the laboratory. The cost of this is very low, on a par with the cost of developing a single drug in the present regulatory environment. If SENS works, which is to say significantly extends the life and restores the health of old animals, then we can probably throw programmed aging theories out of the window in short order. Theory is theory, but proof is proof.
The SENS research community is not so many years away from being able to do just this for some aspects of the SENS program. The more money we can raise for their research, the faster it goes.
The Russian biogerontology community is very much ground zero for new work on programmed aging, and with language barriers lowering and increased scientific collaboration between regions a lot more of their publications come to my attention. The open access journal Biochemistry (Moscow) regularly runs issues packed with papers on aging as an evolved genetic program. This is the case again in Volume 78(9), and as always it makes for interesting reading even while disagreeing.
Arguments Against Non-programmed Aging Theories
Until recently, non-programmed theories of biological aging were popular because of the widespread perception that the evolution process could not support the development and retention of programmed aging in mammals. However, newer evolutionary mechanics theories including group selection, kin selection, and evolvability theory support mammal programmed aging, and multiple programmed aging theories have been published based on the new mechanics.Some proponents of non-programmed aging still contend that their non-programmed theories are superior despite the new mechanics concepts. However, as summarized here, programmed theories provide a vastly better fit to empirical evidence and do not suffer from multiple implausible assumptions that are required by non-programmed theories. This issue is important because programmed theories suggest very different mechanisms for the aging process and therefore different mechanisms behind highly age-related diseases and conditions such as cancer, heart disease, and stroke.
Phenoptosis as Genetically Determined Aging Influenced by Signals from the Environment
Aging is a complex and not well understood process. Two opposite concepts try to explain its causes and mechanisms - programmed aging and aging of "wear and tear" (stochastic aging). To date, much evidence has been obtained that contradicts the theories of aging as being due to accumulation of various damages. For example, creation of adequate conditions for the functioning of the organism's components (appropriate microenvironment, humoral background, etc.) has been shown to cause partial or complete reversibility of signs of its aging.Programmed aging and death of an organism can be termed phenoptosis by analogy to the term apoptosis for programmed cell death. The necessity of this phenomenon [has] been justified by the need for population renewal according to ecological and evolutionary requirements. Species-specific lifespan, age-dependent changes in expression pattern of genes, etc. are compatible with the concept of phenoptosis.
However, the intraspecific rate of aging was shown to vary over of a wide range depending on living conditions. This means that the "aging program" is not set rigidly; it sensitively adjusts an individual to the specific realities of its habitat. Moreover, there are indications that in rather severe conditions of natural habitat the aging program can be completely cancelled, as the need for it disappears because of the raised mortality from external causes (high extrinsic mortality), providing fast turnover of the population.
Post-Reproductive Life Span and Demographic Stability
Recent field studies suggest that it is common in nature for animals to outlive their reproductive viability. Post-reproductive life span has been observed in a broad range of vertebrate and invertebrate species. But post-reproductive life span poses a paradox for traditional theories of life history evolution. The commonly cited explanation is the "grandmother hypothesis", which applies only to higher, social mammals.We propose that post-reproductive life span evolves to stabilize predator-prey population dynamics, avoiding local extinctions. In the absence of senescence, juveniles would be the most susceptible age class. If juveniles are the first to disappear when predation pressure is high, this amplifies the population's risk of extinction. A class of older, senescent individuals can help shield the juveniles from predation, stabilizing demographics and avoiding extinction. If, in addition, the life history is arranged so that the older individuals are no longer fertile, the stabilizing effect is further enhanced.
During the last decade, evidence has been accumulating supporting the hypothesis that aging is genetically programmed and, therefore, precisely timed. This hypothesis poses a question: what is the mechanism of the biological clock that controls aging? Measuring the level of the advanced glycation end products (AGE) is one of the possible principles underlying the functioning of the biological clock. Protein glycation is an irreversible, non-enzymatic, and relatively slow process. Moreover, many types of cells have receptors that can measure AGE level. We propose the existence of a protein that has a lifespan comparable to that of the whole organism. Interaction of the advanced glycation end product generated from this protein with a specific AGE receptor might initiate apoptosis in a vitally important non-regenerating tissue that produces a primary juvenile hormone. This could result in the age-dependent decrease in the level of this hormone leading to aging of the organism.
I pay tribute to the aims of Aubrey de Grey, but from a medical perspective, I doubt that it isn`t very likely to see a successful tanslation of the SENS idea in to clinical practice. For example, MitoSENS has to target every single cell, including the finetuning of transcriptional regulation according to variable demands within the ochetstra of cell metabolism. This won't happen within our lifetime.
However, if there will be an effective method of slowing down the aging process, e.g if you age the equivalent of one day in a whole week, our functional lifespan would be expanded substantially.
Furthermore, if aging is programmed by epigenetic changes, eg. DNA methylation, an epigenetic reprogramming approach similar to the method of induced pluripotent stem cell generation would have a great chance to produce true rejuvenation.
I always like to go back to the case of neurons. They've been transplanted from one species of rodent to another longer lived and actually survived for longer than the original host species. This shows that the neuron's maintenance mechanisms actually exceed that required for some species lifespans.
Evidence suggest that neurons can survive in humans for over 120 years, and in other mammals for over 200 years. The neuron is a cell with a very high metabolism, how is it managing this? Clearly some mechanism must be in place to deal with mitochondria quality, protein quality, etc for centuries. It would be interesting to see what are the actual mechanisms involved, perhaps there already is naturally adequate mechanisms that only need to be ramped up. Or perhaps some of the sens suggestions have had to be implemented.
Either case, solutions for some of the sens proposals if it is necessary should be there, and if not the necessary genetic adjustments for indefinite lifespan of cells should be there(a neuron in an animal that lives centuries probably exceeds that animals max lifespan and is likely negligibly senescent). Intraspecies Genetic analysis of maintenance genes between different tissues and genomic comparison between neurons of the longer lived species should provide an answer.
How old do you think we are, Tobias? MitoSens is absolutely certain to happen within our lifetimes, it's making great progress. Obviously we don't have to target every single cell to have a rejuvenation effect, rejuvenating half your cells would still make you a lot younger overall. And MitoSens is a PERMANENT CURE for mitochondrial aging... Any cell that you reach once will have its mitochondria never age again. If you can make someone ten years younger you can always come back in ten years with a more advanced delivery method that will fix another fraction of their cells, until they are all fixed. They have already tested mitosens and it works even without getting the gene expression right or regulated at all. There's no need for perfection.
Slowing aging as much as you say is obviously impossible in humans. You are trying to mess with a super complicated poorly understood system and make it run at 700% efficiency. But undoing some of the aging damage that already happened is quite easy and our functional lifespan would be extended forever.
Obviously there's no point in programming something that's going to happen anyway. Aging is something the body has to actively fight against, not something it has to try to trigger. Things naturally wear out.
I am in the aging as damage camp. But I do not think the programed aging camp will ever go away. It is a metaphysical construct which can not be disproven, any new advance will just be incorporated into a modified programed aging platform.
"MitoSens is absolutely certain to happen within our lifetimes, it's making great progress. "-Carl
I'm not very familiar with the mitochondrial changes related to lifespan in mammals. Have mitosens-like solutions had to be implemented by nature going from mice to human neurons(cells going in species from years to decades lifespan)? how about in bowhead whales which iirc evidence suggest can last over two centuries?
If nature has been slowly implementing mitosens like solutions then more complete mammalian implementations of mitosens should exist in even longer lived mammalian species.
If no mitosens solution has been implemented by nature going form mouse to human to bowhead whale, then it stands to reason an alternative must exist to preserve mitochondrial quality.
I'm scratching my head here, wondering if the debate is about seeing the same reality from different angles, as with blind men describing an elephant.
In any homeostatic system of vast complexity, wouldn't aging have to appear to be programmed? That triggers get sent forth to gently slow down HGH production and the like?
Would this set of aging timing/triggers bring back to mind the claims of extreme life extension by Odens involving DNA injections? I understand that no one has ever re-attempted this - but do these apparent observations of 'programmed' aging justify another look?