Frame Magazine


WHAT EXACTLY CAUSES AGEING ?

The root causes of aging begin at the molecular and cellular level. Pioneering scientist Leonard Guarente explains how aging works, why it leads to a decline in health, and what can be done about it. Look at a map of the world 200 million years ago and it looks nothing like it does today. What was once a giant continent called Pangea is now entirely different: seven separate continents, with oceans and mountain ranges and even different climates. But it didn’t happen all at once; it happened over time, and scientists now know it was caused by the subtle shift of tectonic plates beneath the earth’s surface that changed the world, and continues to change it, forever. Something similar happens as humans age. Subtle shifts beneath the surface, inside and among our cells, cause a chain of degradation that manifests in various forms: less energy throughout the day, fine lines around the eyes, poor vision, graying hair, aches and pains, and ultimately the chronic diseases associated with aging. But scientists now know not just that time changes everything as humans age, but how time changes everything as humans age. “Aging is not one thing that’s going wrong, it’s many things that go wrong at the same time, in a way that they reinforce each other in their decline,” says Leonard Guarente, director of the Glenn Center for the Biology of Aging Research at MIT and founder of Elysium Health. “I think most people think of it later on in life in terms of their own condition, whatever aging unleashes in them. Few people think of it down to the cellular level.” Historically, the knowledge of aging at the cellular level may have been irrelevant, but today scientists understand enough about how aging happens that we may soon be able to age better — or even slow down or reverse some aspects of aging.

 

– Why We Care About Aging: First, it’s important to understand that while aging is the leading risk factor — that is, your risk goes up with age — for multiple chronic diseases, like cancer, diabetes, and cardiovascular disease, aging is not classified as a disease itself. But the medical community is beginning to recognize that the relationship between aging and chronic disease is intimate: In 2018, the World Health Organization (WHO) added an extension code for “ageing-related” disease to its 11th revision of the International Classification of Diseases for Mortality and Morbidity Statistics, or ICD-11. This new revision defines “ageing-related” as “caused by pathological processes which persistently lead to the loss of organism’s adaptation and progress in older ages,” and the code can be used by doctors or nurses on patient charts to recognize aging as a risk factor for disease. This addition to the ICD-11 could help position age as something that can be treated, ideally leading to therapies and interventions. In other words, while we won’t soon be saying that we’ve “come down” or “developed” a case of aging, it may be increasingly useful to look at it that way if we can pinpoint each of the many things going wrong on the level of molecules and cells. And this is exactly what scientists, including Guarente, are working on.

 

– Aging Happens on the Cellular Level: “Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death,” according to a 2013 review paper, “The Hallmarks of Aging,” in the journal Cell. This paper pinpointed nine specific signs of aging, each one potentially more complicated and foreign than the next, at least to the general population. The nine hallmarks are, according to the paper: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. If this sounds like jargon, that’s normal. Cellular health and cellular damage are complicated, which is why it’s taken so many years to even reach a point of attribution when it comes to the causes of aging. One hallmark that’s most straightforward to understand is mitochondrial dysfunction. The mitochondria are organelles inside each cell, and a site where respiration occurs. The majority of the cell’s ATP, or energy, is made in the mitochondria. “With aging, mitochondria start to decline in function,” Guarente says. “What’s probably happening is that the typical repair processes in place start to lag behind with the dysfunction, and at that point the mitochondria become less efficient and actually produce damaging toxic substances called reactive oxygen species, which inflict more damage on the mitochondria and other parts of the cell. And so you have this feet-forward loop where mitochondria are going down hill and the cell is going downhill as well.” Dysfunctional mitochondria contribute to a variety of health issues. One example is Alzheimer’s, a neurodegenerative disease associated with aging. A 2017 study in mouse models of Alzheimer’s found that enhancing mitochondrial function reduced amyloid plaque formation and improved overall brain function. The mitochondria are the so-called “power plants” of the cell, but they don’t just give us energy to make it through the day without falling asleep. They power our biological processes. If your mitochondria are not functioning, your cellular power plant is depleted, and the rest of your body can’t carry out everything it needs to do to keep you healthy. So as a result of just one hallmark of aging, others spin out, too, cascading into a constellation of cellular damage. Remember, Guarente says that aging is many things going wrong at once in a way that they reinforce each other. That’s what these hallmarks are doing: working collectively to cause damage. “The way I view it, one has to look at an intervention that affects all of those and not just one of them,” Guarente says. And that’s the looming question: What do we do with all this information?

 

– Ongoing Research to Slow Aging: Guarente says that “The Hallmarks of Aging” paper did an excellent job summarizing what declines and falls apart with age but not as much about what we can do about it, and that’s frankly because not a ton can be done right now. However, scientists and researchers are hard at work trying to figure out just what will work. And we may not be far off. “I think the important things that are going to emerge from today’s research, we don’t know,” says Guarente. “That’s what defines a breakthrough, you don’t expect it until it happens.”

 

Six promising areas of research related to slowing aging:

1) Mitochondrial Function: Johan Auwerx, MD and PhD, is a professor at the École Polytechnique Fédérale and directs the Laboratory for Integrated and Systems Physiology (LISP), where he’s studying how diet, exercise, and drug intervention, among other things, could positively affect mitochondrial function.

2) Reprogramming Cells: There’s promising research from Shinya Yamanaka, Guarente says, who won the 2012 Nobel Prize in Physiology or Medicine with John B. Gurdon, for discovering that mature cells can be reprogrammed to become pluripotent cells, or immature cells that could theoretically be reprogrammed for a new use. Labs are continuing to study how this technique can best be applied to humans from a therapeutic standpoint.

3) Simple Lifestyle Changes: Harvard researchers identified five lifestyle habits that can help you live a decade longer: Exercise at least 30 minutes a day, maintain a healthy weight (a BMI between 18.5 and 24.9), drink less (no more than 5 oz. of wine a day for women, 10 oz. for men), eat a healthy diet, and never smoke. The conclusions came from 34 years of research and could prolong life by 14 years for women or 12 years for men.

4) Senolytic Therapies: Other researchers are also investigating how to target the hallmark senescence — cells that stop dividing as part of the biological process and wreak havoc on cellular health — with senolytic therapies that are offering promising results, like improved heart function in mice and a partial reversal of age-related osteoporosis in mice.

5) Calorie Restriction: Another promising, oft touted intervention is calorie restriction, known variously — and each with a specific regimen and its own particular benefits — as time-restricted feeding, intermittent calorie restriction, and periodic fasting. Calorie restriction has long been researched as a key to longevity, and its benefits have begun to permeate mainstream culture, with celebrities like Hugh Jackman, among others, praising its benefits.

6) NAD+ Supplementation: Researchers are studying NAD+, a coenzyme that declines with age. Animal research shows NAD+ supplementation can improve muscle function, increase DNA damage repair, and improve cognitive function. Human research, including Elysium’s own clinical trial, shows that NAD+ can be increased and sustained over time. Scientists theorize that increasing NAD+, which also activates sirtuin proteins, may offer benefits similar to those accrued with calorie restriction. (Source: Elysiumhealth.com)