Let’s face it, getting older sucks, and not because of all the extra candles on the birthday cake. Getting cake and presents every year is great, but the loss of health and independence isn’t a particularly good birthday present. (Wow, what’d I get this year? Just what I didn’t want: sarcopenia and hearing loss!)
Given the downsides of aging, it really is surprising how little people talk about it beyond the odd grumble or even as a joke. Normally, it’s to complain about the aches and pains that gradually appear as the years roll by, as we find it harder to walk up the stairs and “bright-eyed and bushy-tailed” turns into “cloudy-eyed and with an aching back”.
That’s not even the serious side of aging, which involves the gradual loss of independence and the age-related diseases that first rob us of our quality of life before they get around to killing us. The serious part is the horror of Alzheimer’s and the loss of self that it brings, the heart disease that cripples us, the frailty that steals our independence, and the lurking threat of cancer that rises dramatically as we age.
Many people make light of aging and pass it off as simply being part of life, believing that there is nothing they can do about it. That has certainly been true for the entirety of human history, but how we consider and treat aging may be very different in the near future, as could life expectancy.
The sometimes bizarre search for the fountain of youth
While our understanding of what aging is and how it works is advancing rapidly, this has not always been the case, and history is filled with some hilarious examples of how people tried to defeat aging or even death using some really crazy ideas that, in hindsight, were never going to work.
For example, the first emperor of China, Qin Shi Huang, wanted to live forever. Born in 259 B.C., he is perhaps best known for unifying China and was buried in a huge underground palace complex surrounded by an army of terracotta warriors to serve him in the afterlife.
However, he was known to have ordered an official search for ways to achieve immortality and even went as far as taking mercury pills to live forever. Of course, modern science knows that mercury is highly toxic, and it is likely that his own “immortality pills” killed him at age 39 – while the three assassination attempts did not!
Another strange attempt was tried in 1889 by a prestigious scientist by the name of Charles Édouard Brown-Séquard. At the time, scientific knowledge was still very limited, especially our understanding of aging and how the body worked. Charles announced that he had discovered an elixir of youth that could restore youthful vitality to anyone using it.
The source of this “elixir” was, in fact, extracts of dog and guinea pig testicles that he had been injecting into his thigh, and he claimed that using it made him stronger and more vital and that it had even cured his impotence! Even with the limited knowledge of the time, his claim was viewed with skepticism, especially by medical professionals. However, given his prior standing as a scientist, it started a craze, and members of the public eagerly began injecting this testicular extract into themselves.
Of course, the elixir did not actually work, and tests versus a placebo showed that it had no effect nor did it contain significant amounts of active ingredients that could possibly explain the claimed results. Needless to say, Brown-Séquard, who had patented and was selling his solution by then, ended up discredited, and he and his business were effectively run out of town on a rail. Unfortunately, for Brown-Séquard, injecting extracts from animal testicles was not a ticket to eternal life; it was just a fast way to ruin his reputation and live the rest of his life in quiet anonymity.
Seeking eternal life versus reality
People have done a lot of wild and wacky things in their search for eternal youth, but thankfully, science has come a long way since then, and we know a lot more about how aging works than some of these ill-fated experimenters did.
However, before we take a look at some of the exciting, real-world therapies in development that might change how we age, we should probably clear up a common misconception.
Real aging research is not about achieving “eternal life” or “immortality”. The goal is to find effective cures for Alzheimer’s, Parkinson’s, cancer, heart disease, and so on. Put simply, this is medicine with the ultimate goal of ending age-related diseases and the suffering that they bring.
Of course, if all age-related diseases were brought under effective medical control, this would almost certainly lead to substantially longer and healthier lives. However, health, independence, and longevity are good things, as they give us more time to spend enjoying the company of loved ones, traveling, and partaking in hobbies – which is always something worth striving for. This is the ultimate goal of the very real therapies under development that could potentially help us to actually live longer and healthier lives.
A new way of treating age-related diseases
While aging was once thought to be a one-way street, a process that could not be reversed, more and more scientists are now convinced of the plausibility of delaying or reversing aging itself in order to prevent age-related diseases.
According to the widely cited 2013 paper The Hallmarks of Aging, aging consists of nine individual but linked processes that cause the familiar diseases of old age to develop.
- Genomic instability: Damage to nuclear and mitochondrial DNA by free radicals, radiation, and mutagens.
- Epigenetic alteration: Modifications in gene expression, turning on pro-aging genes and shutting down youthful ones, leading to system-wide loss of function.
- Telomere attrition: Wearing down of the protective caps on chromosomes.
- Loss of proteostasis: Deregulation of the mechanisms responsible for protein folding and recycling, leading to the accumulation of harmful by-products.
- Deregulated nutrient sensing: Deterioration of the cell’s response to nutrients, leading to impairments in energy production, cell growth, and other essential functions.
- Mitochondrial dysfunction: Damage to the DNA stored in the mitochondria, resulting in reduced efficiency in energy (ATP) production, an increase in oxidative stress, and the contamination of other mitochondria in a chain reaction.
- Cellular senescence: Accumulation of senescent (non-dividing) cells in the body, impairing tissue function and increasing inflammation.
- Stem cell exhaustion: Depletion of stem cell reserves, leading to a weaker immune system and inadequate tissue repair.
- Altered intercellular communication: Deregulation of the communication channels between cells, causing chronic inflammation and tissue damage.
Researchers are now developing therapies that might address these hallmarks directly at their roots, thus preventing those diseases from developing at all.
This approach is in contrast to most current medicine, in which we generally wait until we get sick and then treat the symptoms. This is perfectly fine when the disease in question is an infectious one, such as a cold, but it is of limited use when it comes to age-related diseases, because the underlying problems are still there and treating the symptoms will not cure them.
The other tantalizing thing to consider with this new approach is that it could also potentially treat or prevent multiple age-related diseases at once because they have a common source: the hallmarks of aging. For example, senescent cells have been implicated in multiple diseases, so their successful removal has very broad implications for health.
So, how close are therapies that target aging?
So, after separating science fact from science fiction, what’s the actual current state of progress in aging research? Most importantly, when might we see the first therapies based on this new approach?
There are multiple therapies in different stages in development, and some of them may arrive in the next few years, assuming all goes well; let’s take a look at some of these potentially transformative therapies.
Boosting the aged immune system
The immune system keeps us safe from the constant invasion of viruses, bacteria, and other pathogens, helping us to stay healthy and free from diseases. However, the immune system begins to break down as we get older and we become ever-more vulnerable to diseases and infections. To solve this problem, scientists are exploring therapies to regenerate the immune system so that it is better able to fight back against diseases as it did in youth.
One company, resTORbio, Inc. has been busy developing a drug called RTB101, an oral medication that helps boost the performance of the aged immune system by targeting the mammalian target of rapamycin (mTOR) pathway, which acts as a regulator of cell metabolism, growth, and survival. The mTOR pathway is divided into two parts, TORC1 and TORC2. In various animal studies, blocking the function of TORC2 appears to reduce lifespan, which is definitely something you don’t want in any drug!
However, reducing TORC1 activity appears to have some beneficial effects, including improved brain function, a reduction of fatty tissue, and delaying the appearance of age-related diseases.
With this in mind, resTORbio has been testing a combination of RTB101 and another TORC1-inhibiting drug, everolimus, to treat respiratory tract infections in the elderly. This combination improves the immune system, giving it the ability to effectively fight back, rather than attempting to treat individual infectious agents.
The company is already well into human trials of RTB101. In 2018, the company ran a phase 2b trial that returned positive results, showing an improvement in the immune systems of elderly patients in response to respiratory infections. 652 older persons with an increased risk of respiratory infections took part in the trial, and after 16 weeks, there were significantly less people suffering from respiratory infections compared to the untreated control group.
Unfortunately, not everything in medicine is simple, and despite the initial positive results, RTB101 was not successful in phase 3, as it failed to reduce the incidence of respiratory infections in a larger patient group. However, all is not lost, and ResTORbio is conducting trials with RTB101 as a therapy for Parkinson’s disease, urinary tract infections, and heart failure using a different dosage and endpoint. There is plenty of reason to believe that its approach could work, given the correct disease target and dosage.
One of the most vital parts of our immune system is the thymus, the training ground for our T cells, which patrol the body and destroy unwelcome guests seeking to invade.
The thymus does a great job at keeping us healthy and free from disease, but there is a problem. Shortly after puberty, the thymus steadily begins to shrink as the T-cell producing tissue turns into fat and slowly wastes away.
This is a real concern because it means that the older we get, the weaker our immune system becomes, leaving us wide open to diseases. The shrinking of the thymus correlates directly with the risk of cancer; this is why beyond age 50 or so, the risk of cancer rises dramatically. Also, diseases such as flu and other respiratory infections can quickly become life-threatening with a compromised immune system.
Recently, a nine-person human trial demonstrated that it is possible to rejuvenate the thymus, causing it to regrow and produce T cells again like it does in a younger person. Dr. Greg Fahy of Intervene Immune led the study, and he showed that in all the patients, the thymus did regrow, with T-cell producing tissue increasing and fatty tissue being reduced. Obviously, this is still early-stage research, but this is the first demonstration in people that the thymus can be regrown to boost the immune system.
Wnt – Samumed
As we get older, our ability to recover from injuries becomes increasingly worse, and our tissues struggle to repair themselves once damaged. The Wnt pathway is a vitally important pathway that controls the behavior and function of the stem cells in our body, and it ensures that our tissues are supplied with fresh cells to replace those that are lost due to injury, disease, and simply wearing out.
Unfortunately, with advancing age, the Wnt pathway, like many other bodily systems, becomes dysfunctional and stops working properly, leading to increasingly poor tissue repair. Falls and other injuries can often prove lethal or lead to life-threatening complications for older people, and tissue and organ failures are all too common as we get older.
Samumed is a biotechnology company that is developing drugs that target the Wnt pathway to restore it to youthful, healthy function. If successful, this approach would allow the body to resume efficient repair of tissues, and it would replenish aged and failing tissues and organs with fresh, healthy cells supplied by the rejuvenated stem cells.
The company has multiple Wnt-targeting drugs in its development pipeline, including several in human clinical trials right now. Two of its more advanced human trials, which are focused on knee osteoarthritis and androgenetic alopecia, have already returned positive results from phase 2 testing and are now in phase 3; if they are successful, it is likely that these drugs will be available in the next few years.
Samumed is also testing drugs to address Alzheimer’s disease, cancerous tumors, tendinopathy, degenerative disc disease, and idiopathic pulmonary fibrosis. Given that the Wnt pathway is fundamentally involved in all our tissue regeneration, these therapies could potentially address a very wide range of diseases.
We rely on a supply of nutrients from the food and drink we consume, as our bodies convert them into the fuel that cells need to function. However, as we get older, our cells become worse at making energy and sensing nutrients, and they become dysfunctional, which can lead to metabolic disorders such as T2 diabetes and obesity.
Nicotinamide adenine dinucleotide (NAD+) is an important molecule found in every cell in our body. It plays a critical role in energy metabolism, DNA repair, cell signaling and a myriad of other cellular functions; quite simply, life would be impossible without NAD+. While NAD+ can be created by our own bodies using amino acids, the majority of it comes from the food we eat.
Unfortunately, from middle age onwards, the level of NAD+ begins to decline, and our cells become less able to repair DNA damage and produce energy; this opens the door for various diseases to develop, and we lack the energy we once had in youth. Obviously, we’d like to put the spring back into our step.
Researchers at the Sinclair Lab at Harvard have shown that restoring the levels of NAD+ in aged mice reversed many aspects of aging in their cells after a week of treatment with a NAD+ boosting compound known as NMN. Following therapy, the mice became closer to younger mice in their ability to repair DNA damage, and they showed improvements in cognition and physical performance.
NMN is currently undergoing human clinical trials at Brigham and Women’s Hospital to see if the benefits observed in animal studies will translate to humans. If successful, NMN therapy has the potential to delay various age-related diseases and could help address metabolic disorders such as T2 diabetes.
We need a constant supply of healthy, new cells to keep our tissues and organs working, and we have an efficient recycling system that removes damaged and old cells from circulation, allowing fresh, new cells to replace them. However, as we get older, this disposal system begins to falter, and an increasing amount of cellular garbage begins to build up as does an accompanying background of chronic inflammation.
Senescent cells have reached the end of their useful and beneficial life: they cease to divide and no longer function properly, but do not dispose of themselves as they should. Instead, they resist removal and produce inflammatory signals that can damage nearby healthy cells and prevent organs and tissues from effectively repairing themselves. The more of these cells that accumulate, the worse our repair mechanisms become as they struggle to cope with the rising tide of inflammation.
Senescent cells have been linked to a plethora of diseases, including diabetes, cancer, osteoartritis, age-related macular degeneration, glaucoma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, kidney disease, and many more. Researchers are now developing ways to remove senescent cells from the body using a new class of drugs known as senolytics. These drugs and therapies encourage senescent cells to destroy themselves, and their removal appears to be beneficial for health and longevity, as shown in multiple animal studies.
Two human trials of senolytics have already been successfully conducted at the Mayo Clinic with some promising results, and biotech companies such as Unity, Cleara, Senolytic Therapeutics, and Oisin have been further developing and refining senolytics, getting them ready for more clinical trials soon. Senolytics have the potential to be truly game-changing in healthcare, and with the initial results in humans looking positive, there is plenty of reason to be optimistic about their arrival in the near future.
If we can eradicate age-related diseases, how long might we live?
This common question is not easy to answer. Some insurance actuaries have attempted to calculate how long someone might live if age-related diseases were no longer a problem, and based on current known and projected risk factors, the estimate is somewhere around 500 years.
Of course, calculating these things is highly challenging, and with the advance of technology, it is unlikely that risk factors will remain the same as they are now. For example, car accidents are a risk, but safety measures in cars have been constantly improved over the past few decades alongside technology. Things like air bags, autonomous braking, side impact bars, and other innovations that protect the driver have dramatically reduced your chances of being killed in a car accident, and these innovations are continuing to improve.
Given that technology and risk factors are constantly shifting, it is essentially impossible to really put a hard number on how long we might live if age-related diseases were no longer a factor. Trying to work this out is a bit like trying to count ants by looking at an anthill.
Some people suggest that it might even be possible to live indefinitely, given sufficiently advanced medical technology. However, while there is no biological reason why this could not happen, the universe is a dangerous place, and the odds are very much stacked against anyone living forever. A meteorite to the face is fairly lethal, and there are plenty of risks in even just stepping out the door to go to the store.
That said, most people would probably not be opposed to a few more decades of healthy life, more time with loved ones, and more time to do the things we enjoy. While it is impossible to really say how long we might live, given advances in medical technology, and it is fun to speculate on how long we might live if aging were brought under medical control, we should probably focus on ending age-related diseases for now and just see how things go regarding lifespans.
So, when is the future?
Right now, there are many more exciting therapies under development. While many of them are in the early stages and it’s likely that some will fail in human clinical trials, others could overcome these hurdles and become standard medical treatment. While we should remain grounded about these advances, the results so far leave us with plenty of room for optimism.
How medicine thinks about aging and treats age-related diseases is likely to change significantly in the next decade or two. A world without these diseases is a world worth striving for, and in such a world, we might just have the good fortune to enjoy longer and healthier lives. Health is the greatest wealth, so the sooner that world arrives, the better.
This article originally appeared in the German magazine Schweizer Monat: https://schweizermonat.ch/die-wege-zur-langlebigkeit/