Searching for the fountain of eternal youth has been the dream of humanity for millennia. While this is still in the realms of science fiction, anti-aging companies are hoping to tackle aging-related diseases by targeting the underlying biology.
Many Silicon Valley leaders have big ambitions and investments in hunting immortality. However, many biotech companies in the anti-aging field have a more humble aim: helping us to stay healthy as we age.
Age is a big risk factor for several common diseases, including cancer, cardiovascular disease and dementia. By treating the aging process itself, the theory is that you could prevent multiple diseases in one go. Some lucky individuals, known as supercentenarians, experience few health problems until extreme old age, so this aim isn’t as far-fetched as it seems.
The biology of aging is monstrously complex, but researchers have narrowed it down to several principal ‘hallmarks of aging’, which include cells breaking down, lack of stem cells in tissues, and unstable DNA. Most research in the field focuses on treating one or more of these hallmarks.
Last month, many companies and researchers gathered at the Undoing Aging conference in Berlin to share their work in the anti-aging field. I spoke with some of them to find out how close these anti-aging treatments are to becoming a reality.
Replacing old tissue with cell therapy
One fundamental aspect to aging is cell division. Many types of cells in the body are designed to die after a certain period of time, such as skin cells. As they are lost to everyday wear and tear, millions of these cells get replaced every day in a continuous cycle. However, as we age, these cells stop being able to reproduce. This process, called senescence, is believed to underlie the aging process in many tissues.
But there is a certain type of cells, known as pluripotent stem cells, that can theoretically divide forever. “All of us are descendants of a lineage of cells that has lasted for billions of years,” said Mike West, CEO of the US company AgeX Therapeutics.
AgeX develops stem cells as therapies for age-related diseases, such as cardiovascular disease and type 2 diabetes. According to West, treating these diseases with regenerative cell therapy is akin to treating the aging process itself, like replacing old parts with new. “A valid way of keeping cars on the road is replacing one of the components,” he told me.
The company keeps ‘progenitor’ stem cells that can transform into specific cell types that replace lost tissue. For example, AgeX is developing a therapy intended to treat type 2 diabetes by replacing lost brown fat cells.
AgeX is also developing potentially revolutionary drugs to treat the aging process. These drugs are designed to partially revert adult cells back to a regenerative stem cell stage, letting them proliferate and regenerate damaged tissue, just like the mexican salamander.
Telomeres, the ends of the chromosomes, shorten each time the cell divides. When the telomeres become too small, the cell no longer divides and is now senescent. Accumulation of senescent cells in tissues is one of the hallmarks of aging.
Currently in preclinical development for treating coronary heart disease, this treatment has been met with some scepticism from other experts in the field. Some of the big objections put forward are that the aging process is incredibly complex, and that senescence is an unavoidable consequence of cells doing their diverse jobs around the body.
However, West is enthusiastic about the future of the treatment. “Bringing the cells part way back to a regenerative mode in humans has kind of been done in a couple of papers,” he told me. “It’s a new idea for sure and I welcome skepticism. It’s fun to be the only person doing something.”
The long and short of telomeres
Every time an adult cell divides, the protective ends of the chromosomes, called telomeres, get shorter. Eventually, the cells are unable to reproduce anymore, becoming senescent, and aging ensues. The discovery of telomeres and their role in cell aging in the 1980s earned the investigators a Nobel Prize in 2009.
This discovery led to extensive research on the role of telomeres in aging in animals. There are also companies developing telomere-lengthening products as an anti-aging solution, including a controversial gene therapy that was claimed to have lengthened the telomeres of a US CEO. However, according to Joachim Lingner, a researcher at the Ecole Polytechnique Fédéral de Lausanne, this approach is risky.
“I think many companies claim they can manipulate telomere length,” he explained. “But these drugs have not been really thoroughly tested and I have serious doubts that they actually have any effect.”
Another big risk of playing with telomere lengths is the development of cancer, where cells replicate out of control. Shortening telomeres limit the number of possible replications, so paradoxically, this mechanism may be keeping us alive for longer. But the majority of cancers dodge this mechanism, meaning this avenue could be exploited to make new drugs treating cancer.
Lingner’s research group studies the molecular machinery underlying telomeres and their function. The group then aims to compare the telomeres of healthy cells with those of cancer cells.
The group has collaborated with Boehringer Ingelheim to screen potential treatments targeting telomeres, but Boehringer dropped the collaboration. “My attempts to have companies interested in this technology were in fact rather frustrating — I basically gave up,” Lingner told me.
In spite of the limited commercial interest so far, Lingner’s group continues the quest to illuminate the complex telomere system in healthy cells and cancer.
Targeting zombie cells
When most cells become unable to reproduce any longer, they are ‘zombies’. Companies such as Barcelona-based Senolytx are developing ways to slow the aging process by removing these zombie cells from tissues.
“When we’re young, we get senescent cells constantly,” Timothy Cash, CSO of Senolytx told me. “When we get a wound, senescent cells will form, but they will be removed after their job is done. When we get older, for some reason, senescent cells show up throughout the body but they’re not removed.”
The company is developing small molecule drugs that help to clear the zombie cells from tissues in age-related diseases such as idiopathic pulmonary fibrosis. Currently in the preclinical stage, Senolytx is also developing these drugs for combination therapies in cancer, removing senescent cells left by chemotherapy.
Senolytx also has other treatments in the discovery stage. One approach the company is investigating is to stop senescent cells from harming the tissue around them instead of killing them. Another is triggering the immune system to remove senescent cells. The immune system of young people is normally efficient at doing this, but gets worse over time.
“This might happen because the immune system isn’t as good as it was at training immune cells,” Cash told me. “But I think it’s even more likely that the senescent cells have become sneaky and tricky, and have blocked the immune system from clearing them.”
Repairing the mitochondria
Healthy mitochondria are vital for cells to function normally. Unlike other structures in the cell, mitochondria contain their own DNA. However, as we age, mitochondria can become faulty because the mitochondrial genome becomes damaged by mutations.
According to Daniel Ives, the CEO of the UK company Shift Bioscience, targeting faulty mitochondria could be the most effective way to tackle the aging process.
“Imagine that you have a network, where some of the biological hallmarks of aging are better connected than others,” he explained. “Mitochondria are a very central hallmark – out of all of them, the most central. If you can affect the central node, you can have a disproportionate effect on that network.”
Shift Bioscience is developing small molecule drugs that can repair the damage to the mitochondrial genome using a repair mechanism called the ‘shift effect’. The drugs essentially force the mitochondria to compete with each other for nutrients, making sure that only healthy mitochondria are able to survive in the cell.
“The shift effect evolved to get rid of mutations in mitochondrial DNA,” Ives explained. The phenomenon has been identified for many years, but triggering it in cells has only recently been achieved, and is yet to be published.
The company is targeting MELAS, a rare mitochondrial disorder causing dementia, muscle disease and seizures. The lead candidate drug is currently completing preclinical development before undergoing clinical testing in healthy volunteers.
“You probably won’t believe your luck being on that phase I trial,” commented Ives. “Not only are you getting paid, but you’re getting paid to take a drug that potentially has an anti-aging activity. It sounds like the best deal I’ve ever heard of.”
How close are we to an anti-aging treatment?
Anti-aging has recently begun attracting big investments, with giant companies getting involved. Google, for example, has poured money into the US biotech Calico to develop anti-aging treatments. The US company Unity Biotechnology includes the US Mayo Clinic and the CEO of Amazon amongst its investors. “Investor interest in anti-aging has already plateaued,” Cash said. “I would say I can’t see it getting any higher. I think it’s at its peak now.”
That said, targeting aging is currently difficult because it’s not an official disease according to the EMA and FDA. Instead, companies are limited to targeting a specific age-related disease each time with these treatments. The American Federation for Aging Research aims to buck this trend with a planned clinical trial testing the effect of the approved diabetes drug metformin on multiple age-related conditions instead of just one.
Cash believes that it’s time to change the public consciousness to accept the aging process as an official target for drug development. “Maybe in the future, once we have motivated the FDA and EMA to start considering aging as an indication, then we can use these molecules that we’ve found for age-related diseases for aging in general,” he explained.
Another challenge could be the biotech industry’s approach to finding anti-aging treatments. “Companies are investing in each one of the hallmarks of aging. ‘Let’s have a horse in the race for every one of these hallmarks and maybe one will work out,’” Ives said. “This model doesn’t confront the fact that we don’t know everything there is to know about aging.”
Furthermore, there are mixed opinions regarding the feasibility of finding an anti-aging treatment in the near future. Cash was enthusiastic about the prospects. “There’s one camp that thinks aging is a stochastic process involving too many pathways and too many processes, and we’re never going to find a drug to hit all those processes,” he said to me. “I think data – genetic data and pharmacological data in animals – do not suggest that and do not support that. It actually supports that we can hit individual targets and extend lifespan.”
However, Lingner was less confident. “I think one of the major issues in aging are the genetic changes that occur and the epigenetic deregulation that accumulates in cells,” he told me. “This is difficult to reverse. I think it will never be possible, but I may be wrong.”
Many of the anti-aging treatments in development are showing promise in animal models such as worms and mice. While encouraging, this raises a separate issue: these animals differ a lot from humans in the aging process. Any organizations or companies developing treatments have to endure the lengthy clinical testing process to prove that these treatments will make a difference in the aging process in humans.
Until we can see concrete clinical proof-of-concept trials from the many anti-aging biotechs and researchers, we are best maintaining a critical eye. For now, at least, the best way to stay healthier for longer is to eat healthily and exercise regularly.
Source: https://labiotech.eu...r-cell-therapy/
Edited by Engadin, 25 April 2019 - 02:26 PM.
