Laura Deming's Introductory Overview of Aging Research

Laura Deming runs the Longevity Fund, and has a research background in the study of aging. It seems likely that the fund will do well on the basis of having invested in Unity Biotechnology alone, even putting aside any other successes. The article here is a useful overview, with copious references, of the type of work presently taking place in the aging research community. It well illustrates that, aside from senescent cell clearance, nearly everything that counts as a major interest by funding and number of scientists involved is a form of tinkering with stress response biochemistry to modestly slow aging - not addressing root cause molecular damage by repairing it, but rather messing with metabolism to slow damage accumulation. Nowhere near as helpful.

Given what we know, where the data exists to compare outcomes between short-lived and long-lived species, the approach of altering metabolic processes to enhance beneficial stress response mechanisms is not going to move the needle all that far in humans. The results should be exercise-like and calorie-restriction-like in that they have worthwhile effects on long-term health, assuming that the cost of development and treatment is low, but they won't add much more to life expectancy than those two items are capable of achieving - which means perhaps the low end of five to ten years at best in our species, assuming life-long commitment to the intervention. Given that senescent cell clearance is a going concern, and other damage repair approaches such as cross-link breaking should follow in the years ahead, we can hope that the focus of the research community will shift as other approaches prove themselves much more cost-effective and successful.

As you get older, the chance that you will die goes up. As you get older, the chance that you will die from certain diseases also goes up. Why does this happen? A simple explanation would be that, like an old car, you accumulate damage in a random fashion. However, there are many simple things that we can do to make animals live longer. Why? We don't really know. Eating less makes mice live longer. Some genes, when mutated, make mice live longer. A few drugs, approved for human use, also make mice live longer. So what is the study of aging? I sum it up as the following: trying to figure out what kinds of damage accumulate with age, how to reverse that accumulation, and the search for switches that we could flip in human biology to increase lifespan.

In the 1930s, investigators wanted to do an experiment to see if stunted growth rates during the Great Depression might impact lifespan. They tested this in rats by feeding them less food than they would normally eat. To their surprise, this actually made the rats live longer! This was a seminal discovery. For the first time, we changed the environment of an animal to make it live longer than it normally would. Since then, investigators have tried to uncover how this works. While long-term human studies are sparse, investigators have run two caloric restriction experiments in monkeys, one of which showed promising results for an increase in survival.

In papers published in 1983-1993, investigators introduced the concept that a gene could control lifespan. Previously we'd known that caloric restriction could make animals live longer, but scientists found mutant genes that could make worms live longer. The first gene found encoded a protein that is similar to insulin-like growth factor and insulin receptors in humans. In mice, mutating members of both of those pathways can increase lifespan. One of the longest-lived mouse mutants we have today is a dwarf mouse. In one study, people with similar dwarf mutations seemed to suffer less age-related disease than their non-mutated relatives.

A paper published in the 70's showed that linking old and young female mice so that they share a bloodstream increased lifespan. Then, in 2011, a succession of papers came out showing that this procedure and others like it made mice better at remembering things, and improved heart and muscle function with age. These discoveries increased excitement and interest in the field, and lead to a wave of startups. Investigators in the field have proposed many possible causes for this phenomenon. Proteins, small vesicles, or cells in the young mouse cleaning the blood of the old mouse might all be part of the effect. Many companies are trying to figure out whether there is a special protein or molecule involved.

As you get old, so do your cells. But some of your cells get old in a way that is much worse than the others. If the cell refuses to die even when it stops working, and starts secreting signals to the immune system, we call that a 'senescent cell'. What happens when you get rid of these cells? Investigators found that getting rid of senescent cells in normal mice made them live a longer healthy lifespan. Knocking out senescent cells is tricky, because they don't have many unique identifiers. Companies are working to either find things empirically that kill senescent cells, or figure out specific mechanisms by which to try to destroy them.

Your body makes a lot of junk, on the molecular level, and cells need to clean this up. Just increasing the expression of one protein that helps to clean up this junk was enough to make mice live ~17% longer. Cells recycle old proteins and other molecules into a big vesicle, called a lysosome. It contains many proteins, and their job is to chop up old cell parts that it engulfs. Genes for proteins that do work in the lysosome are mutated in diseases such as Parkinson's. So improving this process has immediate relevance to neurodegenerative disease. As the lysosome gets older, more junk builds up in it that it cannot degrade. Finding ways to make more lysosomes, or help lysosomes degrade junk, may be interesting therapeutic avenues to pursue.

You may have heard mitochondria referred to as the 'powerhouses' of the cell. One concept that comes up when people talk about mitochondria is 'oxidative stress' - the idea that if molecules are very reactive, they are likely to interfere with a lot of other molecules in the cell that should be left to their own devices. Weirdly, the story has turned on its head over time. It's true that it is bad to pump an animal full of reactive oxygen species, and that you can make a mouse live longer by increasing the level of proteins that are supposed to clean up mitochondria. But you can also mutate things that should be helping the mitochondria, and end up increasing lifespan! It's counterintuitive, and one hypothesis is that a little bit of stress is good because it forces your cells to put up their defenses and ramp up production of molecules that neuter the reactive oxygen species. But we don't really know.



It is a pity that Laura Deming and her colleagues don't seem to have heard of any of the SENS RF spin off companies. Companies could always use more investment.

Posted by: Jim at January 3rd, 2018 7:01 AM

Yeah, in fact useless FAQ, more 'mainstream' in bad meaning than many classic gerontologists' views. I wrote her and give a few advances but she did not answer. I will write my own soon!

Posted by: Ariel at January 3rd, 2018 1:03 PM

Deming and co have backed Alexo Therapeutics who are developing a antibody to CD47 to try and allow macrophages to better eat cancer without being inactivated. Their twist is that the FC region of the antibody is deactivated, and they hope this will mean that fewer marcophages end up 'eating' red blood cells when combined with antibodies that target cancer antigens, which amp up the regconition of the macrophages.

I'm just a layperson, but this seems like a real gamble. You'd still be blocking the CD47 'don't eat me signal' on RBCs, so they would still get eaten to some degree.

I don't know why someone can't develop a Chimeric Antigen Receptor macrophage instead, where the CAR being stimulated by the cancer antigen blocks the signally cascade from the CD47 receptor (which the cancer cell is using to try and deactivate the macrophage).

Posted by: Jim at January 3rd, 2018 3:27 PM

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