Unravelling Longevity: Disrupting The Twelve Factors That Drive Aging
Image: UnsplashOver time and in a quest to map what actually takes us down the road to decline, researchers have slowly identified twelve hallmarks that bring on the aging process. Whether it be cellular malfunctions to broader system failures, these factors provide a roadmap that allows scientists to analyse the mechanisms that drive aging in our bodies. This article delves into how scientists are striving to go even further, by endeavouring to overturn and look underneath these twelve “stones” that cause our bodies to age over the years. It will also highlight some of the work of the visionary scientists who continue to spearhead the efforts to defeat aging, and the promise this holds for the future. You never know, perhaps age-related decline could very well become a thing of the past.
What Factors Are Widely Recognised as the Twelve Hallmarks of Aging?
| The 12 Hallmarks of Aging | |
|---|---|
| 1. | Genomic Instability |
| 2. | Telomere Attrition |
| 3. | Epigenetic Alterations |
| 4. | Loss of Proteostasis |
| 5. | Deregulated Nutrient Sensing |
| 6. | Mitochondrial Dysfunction |
| 7. | Cellular Senescence |
| 8. | Stem Cell Exhaustion |
| 9. | Altered Intercellular Communication |
| 10. | Chronic Inflammation |
| 11. | Disabled Macroautophagy |
| 12. | Dysbiosis |
First, let’s run through each of these Hallmarks of Aging, explore what is currently being done to combat them, and also identify some of the remarkable minds (and organisations) that have been pivotal in trying to halt these factors… after all their amazing efforts could very well be crucial to helping us all buy more time.
1. Genomic Instability
Genomic instability refers to the increased frequency of mutations within the genome over time. If one likens DNA to an instruction manual for our bodies, over time this manual can develop some errors, which can be described as Genomic instability. This phenomenon is a consequence of the cell's inability to effectively repair DNA damage. This could arise from external factors such as radiation or internal factors like oxidative stress. What is clear though, is that the accumulated damage over time can lead to various age-related diseases, including cancer. This damage also plays a significant role in the overall aging process in general.
The good news is many scientists are on a mission to fix these errors. They are exploring tools to correct these errors and even boost our body's natural repair system. Advanced technologies such as CRISPR-Cas9 also offer promise in directly rectifying DNA anomalies. While, compounds that enhance the body's DNA repair mechanisms or even shield DNA from damage are also being investigated by researchers.
Companies such as Unity Biotechnology focus on therapeutics to extend one’s healthspan by countering cellular dysfunctions stemming from genomic instability.
The SENS Research Foundation is playing a key role by aiming to target ways to address the root causes of aging, including by looking at genomic instability. Renowned biogerontologist Aubrey de Grey, who was formerly the foundation's Chief Science Officer and now runs the LEV Foundation, has long emphasised the significance of genomic maintenance in achieving longevity.
What is clear is the race is on to keep our body's instruction manual clear, readable, and error-free as we age.
2. Telomere Attrition
Gradual shortening of telomeres, which are the protective structures sitting at the end of chromosomes, can cause cell malfunction. If one can imagine DNA as shoelaces, at the end of each shoelace is a plastic cap, called an aglet, that stops it from fraying. In our DNA, these caps are called telomeres. As we age, just as aglets can wear out, telomeres get shorter. This shortening, known as telomere attrition, can cause our cells to work improperly or even stop working altogether.
Significant research is underway to stop this wear and tear, and even rebuild these caps. Scientists are looking at ways to lengthen telomeres or at least slow their shortening, hoping this might help us stay healthier for longer.
Nobel laureate Dr. Elizabeth Blackburn discovered an enzyme called telomerase that can rebuild telomeres.
Sierra Sciences and Dr. Bill Andrews have dedicated research toward activating telomerase, which will hopefully help maintain or even extend the length of our telomeres.
By protecting and repairing the caps of our DNA, it is hoped this will keep our cells functioning well as we grow older.
3. Epigenetic Alterations
Changes in gene expression regulation, without DNA sequence alterations, can lead to erratic gene activity.
Imagine our DNA as a music playlist, where genes the songs with their own volume control. Epigenetics can be described as the system adjusting the volume knobs, this determines which songs play loudly, softly, or are even muted. Overtime as we age this “playlist system” can get out of tune, which often causes some songs to roar loudly when they should be quiet, or others to suddenly go silent when we really need them. These “volume errors” in our genes are what is known as epigenetic alterations.
The great news is that scientists are currently working on a way to recalibrate these controls. By tweaking the epigenetic settings, they aim to correct gene activity, potentially reversing age-related changes.
Dr. David Sinclair, a leading professor from Harvard Medical School is an innovator in the field of Epigenetics. He is known for delving into various ways to adjust our epigenetic settings. Much of his research has been focused on sirtuins, which are a class of signalling proteins involved in metabolic regulation, found to potentially regulate lifespan in various organisms.
Sinclair is also renowned for this work on the compound resveratrol. His research has indicated that resveratrol can activate sirtuins, which could result in anti-aging benefits. This has resulted in significant interest in the compound as a potential supplement or drug for promoting health in aging. Dr Sinclair has also co-founded a number of biotech companies targeted at developing new therapies for diseases of aging and extending our healthspans.
4. Loss of Proteostasis
Our cells constantly produce proteins which are essential for nearly every function in our bodies. An imbalance in protein synthesis and degradation can lead to a buildup of faulty proteins. Proteostasis refers to the delicate balance of creating, folding, and disposing of these proteins. As we age, this system can falter. When proteostasis is lost, misfolded or unnecessary proteins are allowed to accumulate, this can harm our cells and contribute to diseases such as Alzheimer’s. Just like when a machine starts to break down, it can start producing “faulty products”.
In an effort to address this, scientists are looking at ways to enhance the clean-up of our cells. Techniques being researched involve boosting cellular "recycling plants" called proteasomes, or enhancing a cleanup process named autophagy, to efficiently remove these unwanted proteins.
Dr. Andrew Dillin, a professor at the University of California, Berkeley, has been instrumental in understanding the mechanisms of proteostasis, especially in the context of aging. His lab has focused on how organisms sense and respond to stress at the cellular level, and how these responses impact lifespan.
Dr. Richard Morimoto from Northwestern University conducts research focused on the heat shock response, which is a crucial aspect of the proteostatic system, and he investigates how cells respond to environmental and physiological stress.
5. Deregulated Nutrient Sensing
At its core, our body has intricate systems to sense and respond to nutrients, ensuring we get just the right amount for our needs. Impaired cellular nutrient sensing can affect metabolism and growth. This deregulation can lead to various health issues, from diabetes to faster aging.
Scientists are studying molecules and pathways such as mTOR, AMPK, insulin, and IGF-1, that are crucial to how our cells sense and respond to nutrients. Metformin, which is a drug that impacts nutrient sensing pathways is also in the process of being analysed for longevity properties.
Dr. Nir Barzilai is a key advocate for the potential anti-aging benefits of the drug metformin, commonly used to treat type 2 diabetes. He also leads the TAME (Targeting Aging with Metformin) trial, which seeks to understand whether metformin can extend the period of life free of chronic diseases or not.
What is clear is that the goal of scientists here is to recalibrate the body's response to nutrients, which will then hopefully help us all to maintain greater health. This could also potentially extend our lifespans by ensuring our cell function remains harmonious.
6. Mitochondrial Dysfunction
Mitochondria are crucial for producing energy necessary for cellular functions. As we age, these mitochondria can become less efficient or even defective, which can result in a state known as mitochondrial dysfunction. When mitochondria are not functioning properly, cells cannot get the energy they need. This can lead to a wide range of health issues. It can also contribute to many age-related diseases, including neurodegenerative illnesses and cardiac issues.
Scientists are currently researching ways to improve mitochondrial function. This includes the development of drugs that can enhance mitochondrial efficiency, using compounds like NAD+ precursors to boost their function, and even exploring methods to replace damaged mitochondria.
Elysium Health, founded by Dr. Leonard Guarente, who is also the director of the Glenn Laboratory for the Science of Aging at MIT, has developed a supplement called Basis. This supplement contains nicotinamide riboside (NR) and pterostilbene. NR is a precursor to NAD+, a coenzyme found in all living cells and vital for cellular functions. NAD+ levels decline as we age and it is believed by many experts that boosting these levels could result in many health benefits, such as improved mitochondrial function.
Dr. Douglas Wallace at the Children's Hospital of Philadelphia has also made significant contributions to the understanding of mitochondrial genetics and its role in health and disease. Dr. Wallace is regarded as a pioneer in to identifying and characterising mutations in mitochondrial DNA (mtDNA) that are responsible for various human diseases.
7. Cellular Senescence
Cellular senescence can be described as an occurrence where cells lose their ability to divide and function properly. Instead of dying, these cells linger and release substances that can be harmful to neighbouring cells, contributing to tissue dysfunction, inflammation, and many age-associated diseases.
Reversing or mitigating the effects of cellular senescence is a topic that has gained significant attention by many scientists in aging research. The development of drugs called Senolytics aims to selectively eliminate these senescent cells. By clearing out these non-functional cells, this can allow tissue to rejuvenate, which could potentially result in healthier aging.
Dr. Judith Campisi is a leading researcher in the field of cellular senescence at the Buck Institute for Research on Aging and has made remarkable contributions to the understanding of the role of senescent cells in aging and disease.
Dr. Jan van Deursen, was among the first to show that removing senescent cells could delay aging-associated disorders in mice.
Unity Biotechnology, which was co-founded by both Dr. Judith Campisi and Dr. Jan van Deursen, is a company dedicated to developing senolytic therapies to treat age-related diseases. They currently have a number of drugs in their pipeline and being trialled, which ultimately aim to selectively eliminate senescent cells.
8. Stem Cell Exhaustion
Stem cells are the body's natural reservoir for replacing damaged or old cells. The diminished capacity of stem cells to repair tissues is called stem cell exhaustion. As the body's capacity to regenerate and repair tissues is compromised this contributes to the aging process and the onset of age-related diseases.
Researchers are actively exploring ways to combat stem cell exhaustion by stimulating dormant stem cells in the body, transplanting external stem cells, and using molecules to rejuvenate the existing stem cell population.
California Institute for Regenerative Medicine (CIRM) has been at the forefront of stem cell research, providing grants and funding for numerous stem cell-related projects and research endeavours.
The understanding muscle stem cell biology is also a crucial factor because muscle wasting (muscle atrophy) is a prominent feature of aging. Dr. Amy Wagers from Harvard University’s Stem Cell Institute has been a central figure in the field of stem cell biology and regenerative medicine. A significant amount of Dr Wagers’ work has focused on the biology of skeletal muscle stem cells. She has investigated how these cells function, regenerate, and repair muscle tissue, and how their function changes with age.
Addressing stem cell exhaustion is vital for rejuvenating aged tissues. The ongoing efforts of researchers and institutions are paving the way for breakthroughs that may one day reverse this hallmark of aging.
9. Altered Intercellular Communication
Cells constantly communicate with one another in our bodies, and send signals to coordinate processes like growth, inflammation, and repair. However, as we age this communication gets disrupted, which can result in an increased risk of inflammation, decreased immune function, and other age-related complications.
Scientists are working on understanding the intricacies of cellular communication and developing ways to modulate these signals for better health outcomes.
Dr. Jennifer Garrison from the Buck Institute endeavours to understand the mechanisms and pathways of these signals, particularly those that influence aging and age-related diseases. It is hoped that by unravelling these pathways, it might be possible to identify potential interventions to promote healthy aging. Her work also involves studying specific genes, proteins, and other molecules that play a role in neuroendocrine signalling and aging.
Neuroscientist Dr. Tony Wyss-Coray from Stanford University is a leading figure in the study of young blood transfusions. His lab's research on parabiosis (connecting the circulatory systems of young and old mice) demonstrated rejuvenative effects on the brains of the older mice. He is interested in how factors in young blood might rejuvenate older tissues by modifying intercellular signals.
Alkahest, which was spun off from Dr Wyss-Coray’s research, continues to focus on identifying specific factors in plasma that can combat aging. Rather than using full plasma transfusions, they aim to harness these factors for targeted therapies.
By targeting altered intercellular communication, scientists hope to restore harmony within the body's cellular community, potentially mitigating age-related diseases and promoting healthier aging.
10. Chronic Inflammation
Chronic inflammation is a prolonged and persistent state of inflammation in the body. While short-term inflammation is a protective response to injury or infection, chronic inflammation at times can result in tissue damage, increased risk of chronic diseases, and accelerate the aging process.
Scientists have attempted to intercept chronic inflammation through the development of anti-inflammatory drugs, dietary interventions, and lifestyle modifications.
Many researchers have also long emphasised the important role of diet and exercise in reducing chronic inflammation.
11. Disabled Macroautophagy
Macroautophagy, commonly referred to as autophagy, is when the cell's “recycling system”, becomes less efficient, and attempts to breakdown and recycle old or damaged components.
This cell recycling system becomes more problematic as we age, which results in a buildup of damaged cellular components which can contribute to aging and various diseases.
Scientists are exploring drugs and interventions that can boost autophagy, such as fasting or calorie restriction, which have been shown to activate this process.
Japanese Nobel Prize winner Dr. Yoshinori Ohsumi is a cell biologist whose research on autophagy has paved the way for a deeper understanding of cellular health, aging, and disease mechanisms, making him a monumental figure in the realm of cell biology.
12. Dysbiosis
Dysbiosis can be defined as an imbalance in the microbial community, particularly in the gut. Our gut houses trillions of microorganisms, playing a vital role in digestion, immunity, and overall health. When an imbalance occurs, it can lead to various health issues, including digestive problems and chronic diseases. i
Scientist are currently addressing dysbiosis by restoring the beneficial microbial balance. For example, Probiotics and Prebiotics are supplements that can introduce or nourish bacteria to improve health.
Experts also believe that diets rich in fiber and low in processed foods can support a healthy gut microbiome.
Fecal Microbiota Transplantation (FMT) is an example of a revolutionary procedure that is conducted in extreme cases and involves fecal matter from a healthy donor being transferred to a patient to restore gut balance. The procedure has been known to control an infection known as Clostridium difficile (C. diff), by adding healthy bacteria into the recipient’s intestines. There have also been studies recently looking at how FMT could treat Crohn’s disease, ulcerative colitis, and possibly even peanut allergies. This is based on evidence that by transferring good bacteria it could boost the immune system.
The Human Microbiome Project is an initiative by the National Institutes of Health (NIH) to help understand the human microbiome (which are the collection of microbes such as bacteria, viruses and single cell eukaryotes) and the role it plays in human health and disease.
Dr. Rob Knight, who is currently based at the University of California in San Diego, and co-founder of the American Gut Project, is at the forefront of microbiome research. He uses laboratory and computational techniques to further understand its dynamics and implications.
Reversing dysbiosis and maintaining a balanced microbiome is essential for optimal health, disease prevention, and potentially even lifespan extension.
So What Does The Future Look Like? Are These Hallmarks On Borrowed Time?
It is clear longevity science has already begun to enter into an era of dramatic discoveries about human biology, drivers of disease, and aging.
The blunt reality is scientists are starting to figure out so much more about the complex drivers of aging at a rapid rate that has never been seen before.
We have already begun to walk through the door into an era that will produce unbelievable discoveries about human biology.
Thirty years ago, aging wasn’t even considered a real science. However, due to innovators such as Dr. David Sinclair and Dr. Aubrey de Grey, who have been prepared to buck the trend and take up the challenge to openly explore the possibility of reprogramming our biology to halt or slow aging… the reality of defeating this curse is now staring us in the face.
Aging is now increasingly becoming viewed as a curable disease, and scientists are making giant leaps as we speak to help create a happier, longer-lived population.
Thanks to the brilliant minds who are prepared to put the hallmarks of aging under the microscope, more resources are now slowly being put into how they can be overcome as the fight to cure aging gets further traction.
The combined efforts of scientists, researchers, and biotech companies offer hope for interventions and therapies to halt or reverse aging.
Advancements in technology such as artificial intelligence, quantum computing, and brain-computer interfaces, will only further accelerate the discovery of age-reversal therapies and extend our lives further.
A new world is on the horizon, and as a society, we should get ready to live a more youthful and vibrant existence for longer. As more discoveries are made over the next decade or two, the work of these longevity pioneers will ultimately steer humanity into unchartered lifespans.
This extra time could very well give us more capacity to pursue our passions or find greater meaning in life, as we are allowed to take a longer journey in an age of exploration, discovery, and human evolution.
