The Nine Cellular Hallmarks of Aging
This article was originally published as a guest editor post at foodpharmacy.se
By: Graeme Jones, clinical physiologist and CEO at Nordic Clinic Stockholm.
For most of my life, rather pessimistically when I have thought about the aging process, I have thought of the inevitable decline that comes with it. I’ll become frail, my cognitive abilities will decline, and I’ll become more susceptible to various diseases, both infectious and chronic. Working in preventative medicine and health for 15 years, I have extensively tested myself for risks so I can do my best to prevent a problem occurring in the future. For example, I have one copy of the gene that predisposes my brain to Alzheimer’s disease. I could not imagine a worse way to develop chronic disease than to gradually lose my memory of those nearest and dearest, be confused most of the time, and have problems with speaking and writing. Only until recently it would have been assumed all this was inevitable, but research into model organisms indicates that the aging process is more malleable than we once believed.
There is a decline that will come with aging, but the speed at which that decline occurs is something we have some control over. You have probably seen this for yourself. We often see people who appear older or younger than their chronological age. Research into the genetics of longevity indicates that genes only account for 25% of the variation in longevity, with lifestyle making up the remaining 75%. (1)
When we look at what goes on at the cellular level, there are nine of what are called ‘hallmarks of aging’ (2), or basically nine processes that are linked with faster rate of biological aging. As I have stated in a previous blog, the biggest risk factor for any disease is age. How can we therefore slow the aging process? I think this is a fascinating question, as science has really started to uncover how we biologically age. This can lead to us being able to slow down the process and keep chronic disease away for as long as possible, rather than having the last 20 years of our existence with poor quality. What does science tell us so far? Therapies to address aging must seemingly address one or more of these factors, which include:
- Genomic instability – Accumulation of damage and mutations to our DNA: The set of instructions that make us. Various factors increase DNA damage including ultraviolet radiation, alcohol, smoking, and environmental toxins. Though we have DNA repair mechanisms, over time we accumulate damage and mutations to both nuclear (the main part of our cell that carries the DNA instructions that tells our cells how to act) and mitochondrial DNA (the parts of our cell which are responsible for producing energy among other things). Think of DNA like a set of instructions in a book.
- Telomere attrition – Our DNA has to be to be protected and stored if you want the instructions to stay readable just like a book. Chromosomes, which we have 23 pairs in every cell, can be thought of like a bookshelf which holds our DNA. Then we have telomeres, which are tiny little caps on the ends of our chromosomes that help protect them. Similar to the caps on the end of a shoestring, they prevent our chromosomes from being fused together as well as protect them from oxidative damage and shortening during replication. However, these protective factors cause telomeres to shorten over time. When they get too short, cells commit a form of programmed suicide called apoptosis.
- Epigenetic alterations – Though genes function as our blueprint, epigenetic modifications (things from our environment that alter gene expression) determine which genes are on or off. As we age, there are changes to epigenetic modifications that cause noise in the system, similar to scratches on a CD.
- Loss of proteostasis – Healthy cells require constant maintenance to the cellular machinery. This includes making the proper proteins, ensuring that they are properly folded, and degradation of damaged proteins. With age, protein homeostasis is lost leading to intracellular junk.
- Dysregulated nutrient sensing – Nutrient sensing pathways dictate cellular functions such as anabolism or catabolism (anabolism is when the body is more in a building up/repairing state, such as during sleep. Catabolism, like during a workout, or fasting, is when the body is breaking down). As we age, these pathways favor anabolic processes, which generally speed up the aging process and promote such negative processes as cancer.
- Mitochondrial dysfunction – Mitochondria are the powerhouses of our cells, generating more than 95% of cellular energy. During the process of making ATP (the main energy molecule produced in our cells from food and oxygen), our mitochondria make free radicals (a by-product) that cause oxidative damage to our mitochondrial DNA, which further increases free radical production. As we age, this is magnified as we accumulate mutations to our mitochondrial DNA.
- Cellular senescence – A process that protects against cancer in the short term, cellular senescence prevents cells that are too damaged from replicating (we do not want more copies of damaged cells). Rather than removing the cell via apoptosis (think of this like a programme that deletes dysfunction cells), cellular senescence allows the cell to remain but prevents it from creating daughter cells. Though protective in its design, these cells unfortunately secrete factors that negatively affect the function of neighboring cells.
- Stem cell exhaustion – Stem cells replace old cells when they die. Each organ and tissue contains a pool of stem cells that help maintain proper function. Think of stem cells like a substitute in football, hockey or whatever sport – they take over when one person needs replacing.
- Altered intercellular communication – During aging, communication between cells becomes disturbed. This includes changes in hormonal and neurotransmitter signaling as well as the increase in inflammation known as inflammaging.
There is a lot of overlap between these nine hallmarks of aging. For example, nutrient sensing pathways control DNA repair, cellular senescence, stem cell exhaustion, proteostasis, mitochondrial dysfunction, and epigenetic alterations. Furthermore, nearly all therapies to improve aging in model organisms work through nutrient sensing pathways as seem to give the most reward. In future blogs we’ll cover each of these pathways, how they improve aging, and what you can do in everyday life to control them to your advantage if you wish to slow down your rate of aging.