Health Extension at Mithril

Yoga instructor Bette Calman, 83

Yoga instructor Bette Calman, 83

Health Extension Salon held a fundraising dinner at Mithril Capital in the Presidio this week.  This is definitely my favorite monthly meeting these days.  Mithril is an investment firm that funds growth companies tackling tough problems.  They seem to be putting cash into later rounds of funding, as opposed to initial startups.  This is a Peter Thiel fund, so I was particularly interested in this venue.  I find Thiel’s arguments on the stagnation of innovation to be fairly compelling, and I am eager to see if he can use his mountains of cash to trigger innovation in areas where it is most needed.  Thiel’s former PayPal partner, Elon Musk, has grabbed the space and automotive industries by their throats and is giving them the vigorous pummeling they both so sorely deserve.  I wonder what further tricks Thiel has up his own sleeve.

As is his wont, Health Extension founder Joe Betts-LaCroix opened the evening with an update on current events.  This was a dinner talk, so Joe gave his updates while the attendees clanked their plates and silverware together noisily.  But far be it from me to criticize the table manners of the other primates gentlefolk in attendance.  Anyway, Joe brought up an encouraging piece of science in a recent study by Hannum and Guinney et al. that uses methylation profiles as a way to measure aging.  This might be a big deal since there aren’t very good ways to measure aging at a biological level right now.  Joe often points out how useful a metric like blood pressure has been as a proxy for cardiovascular health.  A drug that targets blood pressure can now be approved by the FDA as a treatment for your heart.  If a similar metric can be found for aging, a drug that targets that metric could theoretically be approved by the FDA as a treatment for aging.  (Assuming aging is even acknowledged as a disease by the FDA, that is.)  So Hannum and Guinney’s work is a big step in the right direction if the findings hold up.

Their goal is to compile a database of longevity compounds…  Databases of this sort are very important because there is such a vast amount of research out there that much of it is overlooked by the researchers who can best use this information.

Joe went on to announce that the Longevity Variants database that was created by interns as a Health Extension project is being submitted to a new journal.  This is a meta-study that analyzed a bunch of studies on genetics and aging and created the most comprehensive database of genetic variants associated with longevity in humans.  So this should be a really useful tool for researchers if they can just get it into a journal to spread the news properly.  On a related note, Health Extension is embarking on a similar project in conjunction with the Buck Institute.  Their goal is to compile a database of longevity compounds that will be comprised of all the studies they can find on how various compounds impact longevity.  Databases of this sort are very important because there is such a vast amount of research out there that much of it is overlooked by the researchers who can best use this information.  Proper curation should help solve that problem by reducing the effort researchers must expend to locate information.  It’s cool to see the Health Extension folks rolling up their sleeves and making this happen.  Curation rules.

Joe then discussed an event called the Bay Area Aging Meeting, which is a biennial research conference.  The organizers were trying to get younger researchers more involved by having them submit research posters, but they had trouble generating excitement.  Then they decided to offer a modest $1,000 poster prize with the stipulation that two of the winners would need to present research that was relevant to humans.  This prize idea was immensely successful and created a buzz.  Many more young people submitted posters, and there was much more interest in them as folks went around trying to guess who would win.  Prizes do seem to be an economical way to encourage much more effort than could be purchased directly with the same sum.  Joe solicited some additional funds for this worthy effort, and several generous folks stepped up and offered to contribute toward a poster prize for the next Bay Area Aging Meeting.  It’s important to support young people who show interest in longevity research, before they get sucked into big pharma and end up squandering their talents to develop erectile dysfunction medicines.

The first speaker was Brian Kennedy, CEO and president of the Buck Institute, which does research on aging.  Brian is not only the president, but he is also a principal investigator, who heads a lab and does research.  He started out by showing a chart of the average lifespan over the past 10,000 years, to highlight the fact that humans have only enjoyed our current, relatively long lifespans for a very short period of time, historically speaking.  So in one sense, the problems of aging that we see today are a new phenomenon, rarely experienced by ancient humans.  He also pointed out that evolution optimizes for reproduction, and that aging only happens when selective pressure breaks down (i.e. humans stop getting eaten by saber-toothed tigers or starving to death during the winter).  Yet, some animals like naked mole rats or clams live much longer than we might expect, so nature does have some tricks up its sleeve to extend lifespans if needed.

Kennedy outlined three major theories of aging: damage accumulation, loss of homeostasis, and antagonist pleiotropy.

Kennedy outlined three major theories of aging:

1. Damage accumulation – This seems fairly straightforward.  Everything breaks down in this world.  Entropy rules.  Yet clearly, living things oppose this tendency by building themselves and self-organizing.   It seems to me that there must be more to this story than parts getting worn down.

2. Loss of homeostasis – This is the balance between the various systems of the body breaking down.  I can’t help but think of traditional Chinese medicine with its idea of yin and yang when I hear of homeostasis.  I am interested to see what grain of truth the empirical testing of traditional cultural wisdom will be able to reveal.  But that’s a different discussion.

3. Antagonist pleiotropy – Err, huh?  I guess this is the idea that some processes which are beneficial earlier in life become detrimental later on.  An example of this is testosterone levels in men.  Higher levels of testosterone are favorable early in life, but they increase the risk for prostate cancer later on.

Kennedy went on to discuss some ways to possibly extend your healthspan.  He brought up calorie restriction and suggested that it has been shown to extend the lifespan of primates.  I need to look this up more because I thought that it had NOT been shown to do this in primates.  I understood that it only works for simpler species.  He also reiterated the importance of exercise for health.  Of course everyone knows this already, but it bears endless repeating for those of us who may not get enough exercise.  Where is my HIIT app?

Kennedy then described the overall architecture of biology research.  He pointed out that the reduced cost of experiments on lower life forms (like yeast or flies) allows for the broad testing of an unbiased hypothesis.  These simpler organisms basically enable a shotgun approach in which scientists can test any ideas they can think of, no matter how unlikely.  Once the results of those studies are in, they point out likely candidates for more expensive research on higher animals like mice or even humans.  This is possible because a surprising number of gene functions are conserved across species.  Yeast has a similar insulin pathway to humans.

Rapamycin, which is normally used as an immunosuppressant for organ transplants, has also been shown to extend the lifespan of mice.

Brian Kennedy went on to talk about this drug rapamycin, which is normally used as an immunosuppressant for organ transplants, but has also been shown to extend the lifespan of mice.  This mechanism has something to do with the TOR pathway.  (Fun fact – TOR actually stands for Target Of Rapamycin.)  Now there are many caveats with rapamycin that should discourage folks from running out and shooting the stuff into their veins.  Extended administration of rapamycin leads to problems with insulin resistance.  But Kennedy was upbeat since there are really two TORs – mTORC1 and mTORC2.  If only mTORC1 is inhibited, the problems with insulin resistance don’t materialize, and Kennedy thinks the Buck Institute has found just the compound to do that.  Further discussion revealed that mTORC1 suppression might interfere with wound healing, but Kennedy maintained that the compound could be discontinued in the event of injury or just used intermittently.  He didn’t share what that compound might be, which might be a good thing since I would be sorely tempted to run out and try it myself.

Kennedy then described a Buck study of longevity compounds.  Four different labs were tapped to suggest a candidate for this longevity study in which they will minutely test the mice to see how aging is affected.  Kennedy was quite proud of their ability to measure functional levels, such as devices that provide microscopic bone cross sections of living mice, and cages that can measure mouse respiration.  They are not finished with the study yet, but one of the compounds is outperforming rapamycin already.  The candidates are all small molecules, one is novel, one is off patent.  I look forward to seeing the results of this.

Where aging research shines is with increasing healthspan, and pharma mostly doesn’t address this. Kennedy argues that this is exactly the type of thinking we need to shift toward.

Kennedy closed with a diagram that contrasted aging research with current pharmacological interventions.  Aging research isn’t effective at treating disease, but that is the entire focus of pharma.  Aging research and pharma can both contribute somewhat to disease prevention.  But where aging research shines is with increasing healthspan, and pharma mostly doesn’t address this.  Treating healthy people to keep them healthy is not in the current pharma mindset.  Kennedy argues that this is exactly the type of thinking we need to shift toward, and I couldn’t agree more.

The final speaker of the evening was Berkeley researcher, Professor Andrew Dillin.  He began his talk by warning the audience that he didn’t give many talks because he really preferred to hide in his lab, but he was an engaging speaker who demonstrated an acerbic wit.  Dillin outlined three main areas of exploration: Alzheimer’s, pain, and obesity.  He began by considering the oldest known human, Jean Calment.  Though he didn’t have access to her medical records, he posited that she seemed to have had no cancer nor any dementia, though she lived to the age of 122 years.  Thus, her body was able to maintain both her genome (which would prevent cancer) and her proteome (which would prevent Alzheimer’s).

Speaking of Alzheimer’s, Dillin referred to a study he led, which showed that mice with slowed aging were protected from Alzheimer’s.  They slowed the aging process by lowering the activity of the IGF-1 pathway, which is sort of like encouraging insulin resistance, and seems that it would induce something like diabetes in humans.  Yet some long-lived people show similar mutations in the genes that regulate this insulin/IGF-1 pathway, so I don’t really understand this mechanism.  Anyway, another finding of the study was that non-Alzheimer’s mice had a similar amount of beta amyloid plaques as Alzheimer’s mice, but that the plaques were more densely packed in the non-Alzheimer’s mice.  This adds evidence that beta amyloid plaques are not the villains they have been portrayed as to date, and might even be protective.  Remember to take every scientific model with a grain of salt, my friends.  This too will pass.

Apparently, reported pain increases with age, so naturally Dillin wondered if the reduction of pain would reduce aging.

Dillin next directed our attention to the connection between pain and aging.  Apparently, reported pain increases with age, so naturally Dillin wondered if the reduction of pain would reduce aging.  What if pain is somehow triggering aging?  Mice with a specific pain receptor called capsaicin knocked out lived longer.  (I was unable to locate this study, but I will keep looking.)  Dillin said it was important that the neurons which connect to the pancreas had that pain receptor knocked out, as they regulate metabolism.  Also, the surprisingly long-lived naked mole rats have no capsaicin receptors.  My notes say that there was some suggestion of CGRP inhibitors (which I guess are being explored for migraines) being relevant to this, but somehow if the neurons that regulate metabolism are feeling no pain, then it may extend lifespans?  Sounds good.  It’s painful enough to exercise and eat properly.  We deserve a break now and then.

The dividends of a successful investment in health extension research will tower far above all of the toys our billionaires might briefly amuse themselves with during their short stint on earth.

As usual, Health Extension delivered a potent dose of exciting longevity science.  Aging is complex, but there are many brilliant researchers attacking this problem.  More money is needed to push this research forward, especially since Larry Ellison from Oracle has withdrawn from the game.  Frankly, I am amazed that more billionaires aren’t rushing to fund this research.  Diminishing marginal utility dictates that the third yacht simply can’t be as satisfying as the first.  Yet, the dividends of a successful investment in health extension research will tower far above all of the toys our billionaires might briefly amuse themselves with during their short stint on earth.  I can only hope that more of these plutocrats will take a look at the science and see that aging is a solvable problem.  Thiel himself seems to have figured this out.  We all stand to benefit if they do.

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