Five compounds that slow down aging may be the key to treating a host of diseases
Slowing down aging and what it means for dementia and other diseases
Slowing down aging and what it means for dementia and other diseases
As Covid began spreading through Wuhan, China in early 2020, it became apparent that it was an old person’s disease. While younger folk did come down with it and many got sick enough to die from it, the risk of severe disease and death skyrocketed with age.
Covid is far from the only disease that tends to afflict the elderly far more than the young. Indeed, all the major killers of today such as cancer and cardiovascular disease as well as diseases that ruin quality of life from Alzheimers to mobility disorders overwhelmingly affect those over 65.
While lifestyle choices such as exercise and eating healthy mitigate risk for many diseases, the reduction in risk is trivial compared to being young. For every point in Body Mass Index (BMI), while the risk of heart disease increases by about 5%, the absolute change in risk is only from about 1% to 1.75%. Meanwhile, by age, every 5 years starting at age 55, the risk doubles. An obese, sedentary 30 year old is several times less likely to have a heart attack than a healthy, active 60 year old.
Cancer, another major killer, increases risk enormously with age.
Almost all neurodegenerative disorders, including the four main ones, Alzheimers/Dementia (AD), Parkinson’s, Huntington’s, and ALS or Lou Gehrig’s disease, are heavily skewed towards older people.
For many years scientists believed that aging was simply the result of accumulated damage from living. The body can only repair itself so well and so naturally ages from what it can’t repair. If this is so, then all these diseases are simply the result of accumulated damage. Spinning the roulette wheel one too many times eventually leads to something incurable and death. There is no way out of it.
One of the theories of aging that came from this idea was the free radical theory which proposed that metabolism generates Reactive Oxygen Species or ROS. These ROS cause damage to the cells that leads to dysfunction. For decades, it was believed that by reducing damage to the body through certain kinds of foods containing anti-oxidants, for example, one could live longer. This turns out to be false. While oxidative damage is correlated with aging, experimental evidence suggests it does not cause aging, and many species find no decrease in lifespan with increases in damage. In fact, sometimes mild oxidative damage from free radicals can increase lifespan by stimulating the release of anti-oxidants.
The free radical theory also doesn’t explain why different species age at different rates. Cats and dogs age five times more quickly than humans. Mice, twenty or thirty times. And fruit flies and nematodes like C. elegans only live weeks. Meanwhile, lobsters are virtually immortal.
In the 1980s and 90s experiments on C. elegans rocked the world of aging science as it was demonstrated that by tinkering with the worm’s genes, its lifespan could be extended many times, up to tenfold from 20 days to 200 days. Genes involved in regulating metabolism and insulin reception in particular seem to regulate the speed at which these animals age.
Similar experiments have been carried out on yeast, flies, mice, and these same mutations appear to alter how long humans live as well. In addition, multiple longevity genes have been identified indicating multiple pathways to living longer. These include insulin signaling, dietary restriction, and even mild mitochondrial impairment.
This is a clear indication that our DNA contains the ability to allow us to live longer and, with living longer, comes a decline of age related disorders as well. Its not that we just last longer but continue to get sick as the damage accumulation theory would suggest. We literally stay young longer with extended lifespan.
These changes need not happen in the womb either. Experiments have shown that modifications made to the worm C. elegans during its adulthood can extend its lifespan. Experiments treating 600 day old mice with a compound called rapamycin significantly increased its lifespan. Methionine restriction in mice also works as well as connecting the vascular system of a young mouse to an old one. In worms, heat stress appears to lengthen lifespan.
During development, decreasing nutrition in mice (by increasing litter size) for 20 days seems to also increase lifespan as well as mutations that affect mitochondrial function.
From all these experiments, scientists now know that aging is not the result of accumulated damage but genetically encoded. In other words, evolution has determined how long each species should live based on the needs of the species as a whole. The primary mechanism flips genetic switches that decrease the stress resistance of the organism as it moves past reproductive age. This decrease in stress resistance opens up the organism to accumulate more damage which leads to functional declines. Many of these switches exist within our genes and may be triggered at different times, causing us to age and to develop diseases from heart disease to cancer to neurodegenerative disorders like Alzheimer’s.
It is clear from an evolutionary perspective that we all have this genetic time bomb and that it is there in order to prevent us from competing for resources with our offspring. By turning off stress and damage resistance, evolution ensures that reproduction is prioritized over maintenance of individual lives.
The question then is, given our interest in preventing disease, can these switches be turned back on so that we do not age as quickly?
The answer is yes. A meta-study of neurodegenerative disorders looked at the following five compounds that can extend lifespan and protect against onset:
Metformin — a 60 year old diabetes drug that regulates insulin reception.
Resveratrol — an anti-inflammatory, anti-oxidant compound found in red wine and purple grapes.
Rapamycin — an anti-fungal, antibiotic produced by soil bacteria, used as an immunosuppressant to prevent organ transplant rejection.
N-acetyl cysteine (NAC) — a treatment for acetaminophen overdoses and an antioxidant.
Curcumin — found in tumeric and part of the ginger family, an anti-inflammatory that decreases ROS.
Using model organisms (creatures bred for the study of diseases) including cell cultures, C. elegans, Fruit Flies (Drosophila), Mice, and some human studies, all of these compounds have shown promise against these four terrors:
Alzheimers/Dementia (AD), a disorder that results in declining cognitive abilities, memory loss, and eventual death, is the most common, affecting 40 — 50 million people on this planet. The risk for AD doubles every five years after age 65.
Parkinson’s is a movement disorder caused by the death of dopaminergic neurons in the brain which are responsible for motor function. It affects 10 million people worldwide, mostly over 65.
Huntington’s is a genetic disorder affecting 1 in 10000 people that typically onsets at age 40, leading to death within 10 — 15 years.
Amyotrophic lateral sclerosis (ALS) affects people 40 — 70 years old and leads to death within 3 years of diagnosis.
I have put together the handy table at the end of the article showing how each compound affects lifespan, AD, Parkinson’s, Huntington’s, and ALS in each organism. You can see that some have mixed results while others are positive. Some studies simply haven’t been done or haven’t completed yet. The results are clear, however, and the race is on the find the fountain of youth.
The beauty of anti-aging drugs is that they don’t just treat one disease. They treat all age-related diseases. Unlike Levadopa, which treats the symptoms of Parkinson’s, for example, an anti-aging drug prevents Parkinsons, cancer, and heart disease all at once.
Why treat age related disease instead of more deserving diseases of the young? One of the problems with treating disease is that we have defeated most diseases that kill young people in the developed world. We have raised life expectancy to the point where children are expected to make it to old age. Infectious diseases like smallpox, typhoid, diphtheria, and so on no longer carry off our young. While there is a great deal of work to be done extending that achievement to the rest of the world, the fact remains that the vast majority of resources are now spent treating diseases caused by aging. By slowing the aging process, we can potentially treat these diseases much more effectively than just trying to manage their symptoms.
One of the drawbacks to this approach, of course, is that people will get old and die anyway, and it will take longer. The purpose that evolution has for causing aging in the first place remains: preventing competition with the young. We already live in a world where too much wealth is trapped in the hands of the elderly. Slowing down aging would make this problem worse. Moreover, it is likely that we would be putting off the problems of old age rather than eliminating them completely.
This opens up the question: what is the right age at which to die? And perhaps an even more disturbing question: what do we do when we must die by choice because there is nothing left to kill us?
I can’t answer these questions but the science is clearly moving in that direction. It will be up to us as a society to figure out how to handle a world where aging is optional.
Kulkarni, Ameya S., Sriram Gubbi, and Nir Barzilai. “Benefits of metformin in attenuating the hallmarks of aging.” Cell metabolism 32.1 (2020): 15–30.
Soo, Sonja K., et al. “Compounds that extend longevity are protective in neurodegenerative diseases and provide a novel treatment strategy for these devastating disorders.” Mechanisms of Ageing and Development 190 (2020): 111297.