The Key To Old Age
Long seen as a fatality or the mere expression of the accumulation of oxidation and genetic damage, aging is increasingly understood as a biological program called senescence, regulated by our genes.
For example, studies have shown that across all species of mammals, each gets around about a billion heartbeats per lifetime. So, not surprisingly, the health of our heart is a key factor in increasing lifespan, as discussed in “New Research Reveals Integral Role of Cardio Fitness in Boosting Health and Longevity.”
This radically changes our perspective on longevity. As if it is a program, maybe we can slow it down or reprogram it. Especially now that we finally have the analytical tools to really understand what is going on inside our cells, with the whole spectrum of multi-omics (genomics, transcriptomics, proteomics, etc.).
This has opened the way in many studies on how to increase longevity of animal models, and to investigate how it could be transferred to humans. In “Innovative Approaches to Improving Human Longevity” we explored a few options:
- Senolytics, drugs designed to kill senescent cells selectively.
- Microbiome optimization (the ecosystem of bacteria in our body).
- Reduction of inflammation and improvement of mitochondrial functions.
- Extreme Caloric Restriction (ECR).
We also discussed anti-aging therapies like epigenetic rejuvenation and telomere resetting in “Aging is a Part of Life – That Doesn’t Mean We Can’t Put Up a Fight”.
Genetic Longevity
One concept that goes one step further is genetic modification. This is obviously a highly controversial idea, as for now, human genetic modification is considered a last resort action only ethical for deadly genetic diseases or cancer.
However, the more we practice genetic modification to save lives, the more this taboo is falling apart. And in parallel, it is becoming clear that some genetic modification could radically increase our lifespan.
This is the insight discovered by researchers at the Duke–National University of Singapore Medical School, National Heart Research Institute Singapore, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Germany), MRC Laboratory of Medical Science (UK), University of Melbourne (Australia).
In a paper published in Nature, “Inhibition of IL-11 signaling extends mammalian healthspan and lifespan,” the researchers found that genetically modified mice could see their lifespan increase by 25% by removing just one gene.
Increasing Longevity With Genetic Manipulation
A key idea of the programmed senescence theory is that aging is mostly a consequence of biochemical programs in the body. The reasons why such a mechanism would even exist are debated, but a few proposed reasons are:
- It’s a side effect of other useful functions.
- It’s an evolutionary tool to renew population genetics.
- The limitation of aging is irrelevant to the species’ survival past peak reproductive age.
Whether aging is a tool of evolution to increase the species’ genetic diversity or not, it still means that we could take over this program and, at the very least, temper it down.
An important caveat will be to distinguish between increased lifespan (longer survival) and increased health span (increased length of healthy life), as it is much less relevant to extend life for its own sake.
Inhibiting IL-11
IL-11 is a pro-inflammatory cytokine of the IL-6 family. Cytokines are signaling proteins that help control inflammation in your body. And we know that inflammation plays a key role in senescence, especially the “ERK–AMPK–mTORC1 axis”, which is initially activated by IL-11.
Source: Nature
The researchers already knew that IL-11 is expressed more with age and is associated with senescence and that the removal of the IL-11 gene improves metabolism in mice. Removing the IL-11 gene also dramatically improved lifespan, especially in male mice.
Source: Nature
The researchers also studied the effect of inhibiting IL-11 in aged mice instead of deleting it from birth. They found that the mice lost body fat, improved their glucose metabolism, increased their muscle strength, and had a more flexible metabolism overall.
Ultimately, the mice without the IL-11 gene not only lived longer, but also were a lot healthier, including at a young age.
The Uniqueness Of IL-11
Many pathways for aging have been studied, and all play a role in the process of senescence. However, IL-11 is somewhat unique in being quite upstream of most other genes involved in aging. This led the researchers to propose that IL-11 acts through many mechanisms simultaneously.
And as these effects are a shared mechanism among not only all mammals but all vertebrate animals, it gives a very good chance it would work on humans as well.
“We propose that the pleiotropic benefits seen with inhibition of IL-11 reflect its modulation of multiple ageing pathways (such as ERK, AMPK, mTOR and JAK–STAT3), as seen using polypharmacy in flie
Inhibition of IL-11 improved deterministic features of ageing that are common among vertebrates (such as frailty and sarcopenia), showing generic anti-ageing benefits at the organismal level.”
One more advantage of IL-11 as a target for “curing” aging is that it would be a lot easier to turn into a cure.
This is because other targets proposed until now are acting on aging, but drugs working on these processes tend to have toxic side effects, greatly reducing their medical applications.
“Inhibition of ERK or mTOR or activation of AMPK by trametinib, rapamycin or metformin, respectively, increase lifespan in model organisms, and such drugs are advocated by some for use in humans. However, these agents have on- and off-target toxicities along with variable, and sometimes detrimental, effects on healthspan and inflammation.
Our data suggest that anti-IL-11 therapy, which has a reassuring safety profile and is currently in early-stage clinical trials for fibroinflammatory diseases, is a potentially translatable approach for extending human healthspan and lifespan.”
Potential Impact
Anti-Aging Drugs
Such a study is just the tip of the iceberg in longevity research. More and more targets for innovative therapies are being discovered and investigated.
The key question will be to decide what to do with this knowledge.
The most straightforward path will be to find chemical drugs or biological therapies like antibodies that can modify the expression of these genes. Like for example the anti-IL-11 antibodies were used to suppress the cytokine in old mice in this study.
This is paradoxically likely to happen in animals before humans, with for example Loyal‘s candidate drugs LOY- 001, LOY-002, and LOY-003 to increase the lifespan of dogs. Loyal is quite advanced in its clinical trials, and the company expects commercialization by 2025 and 2027.
Over time, more complex therapies involving several genes like IL-11 at once are probably to come out as well, as it is likely that they act in synergy. So modifying several metabolic pathways at once might not have results that are additive, but more likely multiplicative.
Genetic Engineering
A more controversial approach would be to modify human genetics. If a gene causes aging, why not get rid of it? If a gene reduces aging, why not boost its expression 10-fold?
Of course, this is not that simple. We are barely starting to understand what these genes actually do in the body. So anything as radical as human genetic engineering will likely stay off limits for at the very least a decade.
This is especially true as the FDA considers aging a “natural process” and, therefore, will be very reluctant to approve treatment, even less gene therapy. So any therapy in this field will likely need to prove its efficiency against actual diseases, like hypertension, heart failure, etc. that are related to aging, but not on “curing aging”.
Increased Longevity’s Impacts
Would we manage to increase longevity, this would however have massive consequences.
The first one would be that we would likely need to completely overall our pension systems. In countries with redistribution, the age of retirement would need to be increased drastically. And in countries with investment-based pensions, the calculus for how large a nest egg needs to be would change completely.
Similarly, how such longevity treatment is achieved would have large social impacts.
If it is a complex and expensive treatment, it could bring a serious social divide, with only the richest able to live longer, increasing further the health divide between social classes and overall inequality issues.
If the treatment is cheap enough, its reduction in healthcare costs for hypertension, heart disease, diabetes, etc., and of course, actually delaying death and adding productive years would likely justify its full reimbursement by the state.
Finally, it could have far-reaching cultural consequences, with older population cohorts living longer and staying influential in both the workplace and politics much longer, potentially aggravating the already existing Western democracies to turn into “gerontocracy” (rule by the elderly).
Investing In Longevity
Longevity is for now a barely emerging market, mostly touched by therapies in other biotech domains, like cancer therapies, stem cell research, etc.
This is nevertheless maybe the ultimate biotech/pharmaceutical product, with virtually everyone on Earth a likely eager consumer, at least for decades until everyone might be genetically engineered from birth to benefit from the same.
You can invest in longevity-related companies through many brokers, and you can find here, on securities.io, our recommendations for the best brokers in the USA, Canada, Australia, the UK, as well as many other countries.
If you are not interested in picking longevity companies, you can also look into ETFs like Global X Aging Population ETF (AGNG), ARK Genomic Revolution ETF (ARKG), or Vanguard Health Care ETF (VHT) which will provide more diversified exposure to capitalize on the growing longevity industry through healthcare and biotech exposure.
Or you can check out our article on the “Top 5 Companies Offering Solutions to Increased Human Longevity”.
Longevity Companies
1. Lassen Therapeutics
As mentioned above, IL-11 is already investigated as a target for therapy in fibrosis, by Lassen Therapeutics. This is because IL-11 is not only a mediator of aging, but also of inflammation through the ERK pathways that lead to fibrosis.
Source: Lassen Therapeutics
Lassen has developed an anti-IL-11 antibody to help with fibrosis. The therapy is now in phase 1 of clinical trials for two diseases: one of the eyes and one of the lungs.
The company is also working in oncology (cancer) on an anti IL-18 antibody, which could reduce the growth of certain tumor types needing the inflammation created by IL-18.
Source: Lassen Therapeutics
Of course, the results in mice we discussed above could give anti-IL-11 antibody a massive market in anti-aging as well. This would need to be confirmed in humans first, but at the very least, the clinical trial ongoing for fibrosis will clarify the safety profile of the antibody.
Would anti-IL-11 antibody be approved by the FDA for fibrosis, it would be a relatively easy task to get a new indication for metabolic diseases, compared to start from scratch with a new therapy.
So investors in Lassen Therapeutics will likely want to mostly count solely on the fibrosis market when valuing the company, but also keep in mind that anti-IL-11 antibodies have the potential to be a very more interesting therapy for other diseases, including maybe all age-related metabolic diseases.
2. Longeveron
Longeveron is working on cell therapies for repairing damaged tissues, degenerative diseases, and the effects of aging.
Its main technology is Lomecel-B™. These are cells collected from young donors’ bone marrows, selected, and then mass-produced. They are multipotent cells called medicinal signaling cells (MSCs) with the capacity to repair damaged and/or inflamed tissues.
Source: Longeveron
A key factor is the regulation of inflammation through the cytokine pathway, the very same molecule class to which IL-11 belongs.
The company pipeline is focused on three different applications for Lomecel-B:
- Hypoplastic Left Heart Syndrome (HLHS), a a congenital birth defect.
- Alzheimer’s Disease.
- Aging Frailty is a low-level chronic pro-inflammatory state separate from normal aging effects.
Early clinical trial results seem to indicate an increasing survival rate for HLHS, a dose-dependent improvement of aging frailty, and improved cognition and quality of life in Alzheimer’s patients.
Lomecel is a stem cell-based method looking to reverse aging or regenerate damaged tissues.
This approach seems successful and shows that aging could be at least partially corrected with the replacement of damaged cells by “fresh” stem cells.
We can also imagine that in the future, genetically modified stem cells could be used to have an even greater impact as we learn more and more about the role of genes like IL-11.
