By understanding the biological changes in our bodies that lead to aging & eventual death, we might have a chance of preventing, delaying or even reversing them. Here’s a layman’s explanation of these changes how we might be able to solve them.
Man has been fascinated about immortality for thousands of years. In ancient Greek mythology, ‘ambrosia’ conferred longevity or immortality upon whoever consumed it. Multiple cultures believed in a mythical spring, ‘Fountain of youth’, that was thought to give everlasting life to whoever bathed in or drank from it.
However, in modern times most people probably think that aging is inevitable. But that’s not true. In the olden days, the average lifespan was much shorter. In ancient Roman times, people could expect to live till only 30 to 35 years. Since 1900 the global average life expectancy has more than doubled and is now above 70 years.
Now researchers understand that death is a technical glitch. Aging is flexible and can be targeted. If we can understand the biochemical changes in our body that lead to aging and eventual death, we can try to stop them. We can delay aging, stop many of its manifestations, and possibly even reverse it. In recent years, a lot of research and funding has been poured into this field of research. The aim is not immortality, but longevity.
We all know a person close to us who suffers excruciatingly from age related diseases. These diseases are devastating for the old people but also for their families. One of the most painful things in the world is to see your parents or grandparents devoid of independence, happiness and energy as they pass their last years lying in bed. Some forget their own grandchildren, some can’t hear anything, some can’t muster enough energy to walk to the washroom themselves. I have had my grandparents at this stage and you feel helpless. That is what longevity and anti-aging research is about. They want to give some healthy years of life back to old people so they can live with dignity and happiness. Thus, longevity isn’t some dystopian villainous scheme to never die but a humble attempt by humans like you and me to get a few more years of happiness and togetherness.
Why do we age?
We all love to claim that ‘age is just a number’. And in many ways it is. However, there are various biological changes that happen to our body as it gets older. If we can figure out and isolate these changes, we might have a chance of preventing or delaying them. In some cases, we can even reverse them!
Thus, the first challenge in our quest for longevity is to understand these multitudes of changes in our bodies when we age which can eventually lead to death. And then we need to isolate each of these and try to prevent or delay these without unknowingly triggering some other harmful change.
Loss of functionality of vital organs
Multiple research has found that several tissue and cell components in our body loose their function over the years. As you can imagine, this leads to a diminished resilience and cell functionality of vital organs. These changes in themselves may not directly cause death but make our bodies weaker. Thus, age is the number one risk factor for many diseases such as cognitive decline, heart problems, cancer, etc. As you get older, the chance that you will die from certain diseases also goes up because of diminished functionality. For example, blood in a young person contains more regenerative factors such as oxytocin. As we get older, this balance is tipped more towards aging factors such as the protein eotaxin. Eotaxin is shown to lead to age-related diseases in which systemic inflammation occurs.
Limit to the no. of cell divisions
Another reason for aging is that some cell types are bound by a certain number of cell divisions that they can undergo. When we are young, these cells have specialized protective caps called telomeres to defend our DNA from damage due to cell division. However, these telomeres shorten with every cell division. Thus, after a certain number of cell divisions, the telomeres are gone. Post that, genetic information is lost or damaged for these cells. This can lead to cell death and organ dysfunctions. It can also lead to the proliferation of these “wrong” cells, which causes cancer.
Aging is caused by and leads to the accumulation of DNA damages at the same time. Free radicals, which are by-products of our regular metabolism, can lead to malfunctions or defective cell divisions. These damages accumulate in our genome. These changes are linked to the decreasing ability of the body to renew injured or defective tissues and organs or to repair biological molecules.
As the research and funding in this field increases, we are discovering more reasons on why we age.
Recent research shows we might be able to delay aging
A lot of fascinating research has been happening with surprising results.
Parabiosis — shared blood circulation
One bizarre technique is called parabiosis, in which blood from a young organism is given to an older organism. Maybe you have seen it as satirical comedy in shows like Silicon Valley. But there’s some science behind it! The experiment was conducted by stitching the circulatory systems of one young and one old mice together. The older mice showed signs of regenerating muscle and other tissues. The old mice also experienced improved activity in the hippocampus, a brain region involved in event recall and spatial memory. It also experienced an increase in connections between brain cells. Moreover, the cognitive and physical performance was also boosted.
Although some attempts were made to transfuse plasma from a young person into an older person, now the focus is more specific. Scientists are trying to identify and isolate the molecular factors responsible for the changes seen in parabiosis experiments. Some of these longevity-related phenotypes can hopefully target specific diseases associated with aging. As mentioned before, with age the aging factors in our body increase while the regenerative factors decrease. However, by comparing the levels of various proteins in the blood of old mice before and after they receive young blood, we can identify these regenerative factors.
Senolytics — removing zombie cells
We learnt that as cells replicate, telomeres shorten at the end of chromosomes. When they run out of telomerase, they can’t make many more copies of themselves. This process correlates to senescence or cellular aging. These senescent cells are damaged beyond repair, secrete signals to the immune system, and no longer able to replicate. When we are young, our body uses a kind of self-destruct process known as apoptosis to remove these damaged cells. However, as we age the natural disposal system slows down to the point where it can no longer keep pace with the accumulation of the unwanted, damaged senescent cells. The “zombie” cells contribute to inflammation, harm tissue repair and regeneration, and significantly contribute to many age-related diseases and cancer.
Multiple research has shown that getting rid of senescent cells in normal mice makes them live a longer healthy lifespan. Thus, a new class of therapies has emerged called Senolytics to make the unwanted senescent cells to stop resisting apoptosis and destroy themselves. Some of the most promising approaches involve selectively killing these cells using senolytic drugs.
However, it isn’t so simple, as you can imagine. No single drug can target every type of senescent cell as different types of cells use different strategies to avoid destruction. We need to identify how many types of senescent cells are there and what pathways they use so that we can develop effective therapies against them.
Mitochondrial biogenesis and Mitophagy
Our mitochondria is tasked with an extremely important job of converting the food we eat into adenosine triphosphate (ATP), the form of chemical energy that our cells use. Mitochondria is also unique in the way that it contains its own DNA. Mitochondrial DNA (mtDNA) produces the important enzymes and proteins needed to provide the primary energy source to our body.
Because of various reasons, mitochondrial DNA damage is more likely to happen and less likely to be fixed than nuclear DNA. Due to these factors, dysfunctional mitochondria is associated with many diseases such as diabetes and Alzheimer’s disease. It is also a hallmark of aging. We talked about free radicals before. Free radicals also are a major cause for mitochondrial damage. However, in small amounts these free radicals are actually beneficial. When there is an overproduction of the reactive free radical, it causes oxidative stress.
Thus, researchers now believe that mtDNA damage is mostly due to an imbalance between mitochondrial biogenesis and mitophagy. Mitochondrial biogenesis can be defined as “the growth and division of pre-existing mitochondria”. Whereas, mitophagy is the “selective removal of damaged mitochondria”. The imbalance between these two processes is caused due to age-related changes in free radical balance in the body. Thus, regulating mitochondrial biogenesis and Mitophagy is one promising solution that many organizations are trying to find. They aim to reduce the level of oxidative stress or induce mitophagy of damaged mitochondria.
Other anti-aging solutions include rapamycin, a drug derived from a bacterium native to Easter Island. Early research has shown increased lifespans of mice by 25% on average. Sometimes, we discover solutions where we weren’t even looking for one. For example, Metformin is a cheap, generic drug to treat type 2 diabetes that turned out to help reducing oxidation stress and inflammation. Stem cell research and regenerative therapies are also one of the most promising areas. This type of technology aims to manipulate a given set of stem cells to regenerate cells or tissues that have lost functions in old age.
But not every solution may be applicable to humans, or the corresponding drug be scalable. So how close are we to longevity therapies and anti-aging drugs?
Anti-aging solutions are coming sooner than you think
The anti-aging and longevity drugs market is booming. Understanding why we age and how to delay aging has become a lucrative field for both big pharma companies and startups globally.
Calico, a Google backed life-extension company, has raised about 2.5 Billion $ till date. They claim they are on an ambitious mission to “better understand the biology that controls aging and lifespan … and … discover and develop interventions that enable people to live longer and healthier lives.” They are in a collaboration with AbbVie, a global biopharmaceutical company, for late stage clinical development and commercialization of novel drugs. Thus, longevity is no longer a futuristic fancy concept but a mainstream reality that will become a trillion dollar market in the decades to come.
Similarly, UNITY Biotechnology raised over $200 million over the last decade from investors such as Jeff Bezos and Peter Thiel. They have since IPOed and recently conducted a clinical trial on humans with a focus on treating osteoarthritis, an age-related disease! Their solution is to utilize senolytic drugs. Now you probably understand the idea of senolytics is to block a survival pathway that senescent cells use to evade being destroyed. Unfortunately, this trial failed to show the desired results. However, it still showcases the fact that these drugs are closer to reality than we think. We now have the first true rejuvenation therapy that directly targets an aging process in human trials.
Senolytics is infact one of the most popular areas of research. The senotherapeutics also includes geroprotectors, which are drugs that may prevent or reverse aging by targeting its cellular triggers such as damage to the DNA. Other key firms in this field of research are Juvenescence AI and Oisin Biotechnologies from the US, Cleara Biotech in the Netherlands, and Spain-based Senolytic Therapeutics. All this competition means that drugs will be faster to market, be cheaper and be more accessible. They have the possibility of absolutely changing the way we age and how we address age-related diseases in the next decade.
One of the companies working towards a better version of parabiosis is Elevian. They claim that injections of the protein GDF11 (growth differentiation factor 11) from younger to aged animals can ultimately treat age-related diseases. Other key players in the human plasma derived therapeutics market include Alkahest, who announced the initiation of a clinical study in June. The basic thesis behind firms in this field is to discover regenerative factors present in blood that have the potential to rejuvenate aged tissues and organs.
Stem cell research is another hot area of research. TreeFrog Therapeutics and Celularity are two startups in this field. AgeX Therapeutics and Lineage Cell Therapeutics were awarded US patent for ‘Method of Generating Induced Pluripotent Stem Cells’ in 2019. This technology can possibly provide a source of starting material for the manufacture of potentially any type of human cell to replace damaged or old cells.
Meanwhile, Epirium Bio is a clinical-stage biopharmaceutical company that is targeting to stimulate mitochondrial biogenesis. Gene therapy is another potential anti-aging therapy. Gordian Biotechnologies have created a multi-modal gene therapy to target age-related diseases. Fauna Bio is identifying genes in hibernating mammals that are responsible for disease protection to pinpoint genetic targets that can cure human disease.
While most of these startups and companies are targeting humans, other initiatives are starting with animals. Loyal is developing drugs that treat the underlying causes of aging in dogs.
Conclusion
The last few centuries and decades are proof that human beings are more than capable of pushing the boundaries of what’s possible. What felt like science fiction 50 years ago is almost a basic necessity now. Thus, it’s only a matter of time before we make serious progress in one of the greatest endeavours since the dawn for humanity — longevity!
