This week we decided to take the plunge and tackle something that gets pretty technical but provides a critical framework for anyone who wants to understand what is driving innovation in the healthspan extension space. We are talking about the “Hallmarks of aging.” These are a number of cellular processes that have been identified as key drivers of the aging process. In fact, our articles often make reference to longevity strategies that are meant to influence one or more of these processes. So, whether you are brand new to the longevity world or have been working on your health for a while, we believe it’s beneficial for anyone interested in living healthier for longer to have a decent grasp of these hallmarks of aging.
A Concept That Shaped Longevity Science
Biomedical gerontologist, Dr. Aubrey de Grey, is credited for creating the framework that we’ve come to know as the “hallmarks of aging”. As one of the forefathers of longevity science, Dr. de Grey pioneered much of the early research on reversing aging and has thus had a hand in shaping the way we now think about the aging process. According to Dr. de Grey, aging is the result of damage we’ve accumulated at the cellular level—a maintenance problem that when left unresolved results in cumulative pathogenic molecular and cellular side-effects, disease, and ultimately cellular death.
Watch Dr. De Gray explain his paradigm-shifting approach to solving aging in this great TedX presentation.
Dr. de Grey’s original framework was divided into seven processes of cellular aging. These were expanded to nine in the seminal 2013 paper titled The Hallmarks of Aging. Authored by a Spanish team led by aging scientist Carlos Lopiz-Otin, this paper has become one of the most cited in the field. Regardless of how many areas we split the aging process into, the core idea remains in line with Dr. de Grey’s original notion: aging is the result of cumulative damage and in order to prevent or reverse aging the damage needs to be repaired.
The nine hallmarks of aging are grouped into three categories: primary causes of damage, responses to damage, and integrative hallmarks resulting from the prior two. Below is a brief description of each one.
Source: López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194 –1217. https://doi.org/10.1016/j.cell.2013.05.039
Primary Hallmarks—The Cause of Damage
As we age, we accumulate DNA damage through factors that occur both outside and inside our bodies. Through our daily interactions as we move about in the world we encounter physical, chemical, and biological factors that can damage our DNA and alter gene expression (e.g., free radicals, exposure to carcinogens and other toxns). We also have internal dynamics that cause DNA replication errors (e.g., point mutations), chromosomal loss or gain, spontaneous chemical reactions, reactive oxygen species, and genetic disruptions caused by viruses. As organisms, we humans have complex DNA repair mechanisms to counteract and salvage most damage that is done to our genome. But as we age, these mechanisms start to fail with increasing frequency, ultimately resulting in alterations to critical gene pathways. As a result, we end up with dysfunctional cells that, if not destroyed by apoptosis or sequestered via senescence, go on to produce age-related diseases.
DNA damage can accumulate anywhere along the genetic strand, but our telomeres are especially susceptible. Telomeres sit at the ends of our chromosomes, are made of non-coding DNA and protect the chromosome from damage. Each time a cell divides, telomeres become shorter. Eventually, the telomeres become so short that the cell can no longer divide, resulting in cellular apoptosis or senescence. Additionally, telomere regions evade our innate DNA repair mechanisms because of protein complexes called shelterins. As a result, telomeres are likely to acquire mutations and DNA damage that persists and can lead to age-related disease or apoptosis.
Go deeper into the impact of shortening telomeres here.
Source: Vaiserman, Alexander & Krasnienkov, Dmytro. (2021). Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives. Frontiers in Genetics. 11. 630186. 10.3389/fgene.2020.630186.
There are a handful of cellular processes that can result in epigenetic alterations affecting the lives of cells. The three most salient are alterations in DNA methylation patterns, histone modifications, and chromatin remodeling. Let’s unpack them.A primary mechanism that induces epigenetic change is methylation—the addition of a methyl group to DNA base pairs or histones. Methylation alters the way our genes are expressed and increases with age. Research shows that methylation is influenced by lifestyle factors like diet, exercise, and stress, suggesting that we have a level of control over the rate at which our DNA is methylated. This links back to our epigenetic age which is based on the rate at which methylation occurs in our DNA, with “older” DNA having a larger proportion of methylated genes. The second mechanism of DNA alteration are histone modifications. These are also caused by changes in methylation and influence important pathways that have been linked to longevity (e.g. the insulin/IGF-1 signaling pathway.) Lastly, chromatin remodeling consists of changes in chromatin architecture resulting in part from the effects of DNA methylation and histone modifications. These changes in turnexpose regulatory sites to transcription factors resulting in altered expression of our genes. While these mechanisms and their interactions are complex, the key takeaway is that a growing body of research points to epigenetic alterations being a key driver of aging.
Click here to read Rhonda Patrick’s detailed review of epigenetics and how it affects the biological age of our cells.
Loss of Proteostasis
The goal of proteostasis is to regulate the body’s proteome through pathways that control the way proteins are made, folded, transported, and degraded. As we age and accumulate DNA damage, the amount of modified proteins in the body increases and our proteostatic mechanisms begin to fail. As a result, proteins are unfolded, misfolded, not degraded, or formed into aggregates. The proliferation of these modified proteins contributes to age-related diseases like Parkinson’s, Alzheimer’s, and even cataracts.
Got a minute? Check out this video about how a loss of proteostasis contributes to Alzheimer’s disease:
Antagonistic Hallmarks—The Response to the Damage
Deregulated Nutrient Sensing
Nutrient sensing pathways are critical for ensuring proper intake of nutrients to the cell. The deregulation of these pathways is a response to the damage we accrue as we age. At the cellular level, DNA damage that results in misfolded proteins can greatly affect the stability of these pathways overtime. An inability to sense levels of key nutrients (e.g., carbohydrates, fats, proteins, vitamins, minerals) in the body decreases cellular metabolism and energy levels, It also impacts cellular growth and repair thus driving age-related decline and disease.
Check out this short video to learn about the specific nutrient pathways affected with age and what it means for your health:
The mitochondria are the powerhouses of the cell, playing a pivotal role in energy metabolism and supplying the cell with the ATP it needs to function. Mitochondria contain their own set of DNA (mtDNA) that is passed on from mother to child. As we age, mtDNA accumulates mutations that affect the way these organelles function. As a result, damaged mitochondria aren’t replaced as effectively by new ones. Energy metabolism is disrupted creating a cascade that affects other functions in the body. And ineffective or incomplete mitophagy (degradation of mitochondria via autophagy) begins to proliferate leaving defective mitochondria to remain active in the cell. Dysfunctional mitochondria in turn increase levels of reactive oxygen species which also promotes cellular aging.
Take a look at this deep-dive into mitochondrial dysfunction to learn more about this hallmark, what types of DNA errors alter function, and what questions still remain unanswered in the research.
Cells naturally age as they divide, but DNA damage and oxidative stress can cause cells to age prematurely. As we mentioned above, our telomeres serve as protective end caps for our DNA and shorten with each round of cell division. When the telomere has been completely degraded, the cell suspends any further replication—senescence—in order to prevent the propagation of damaged DNA. If all senescent cells did was stop dividing it wouldn’t be detrimental to our health; they would be destroyed by apoptosis or degraded by immune cells. However, senescent cells accumulate in our tissues as we age, overwhelming our innate mechanisms to clear them away. The result is a large proportion of cells that have damaged DNA and still living parts of the body. Furthermore, senescent cells affect the behavior of the cells around them and produce proinflammatory factors that prime our bodies for age-related decline and disease.
Check out this video to learn about these senescent “zombie” cells and what it means you’re your health.
Integrative Hallmarks—The Cause of Functional Decline
Stem Cell Exhaustion
The presence of adult stem cells (i.e., hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), satellite cells, and intestinal epithelial stem cells (IESCs)) in our bodies is crucial to maintaining homeostasis and the integrity of our bones, blood vessels, and organs. As we age, we lose stem cells and due to DNA damage are unable to replace them with healthy, fully-functional cells. As a result, we become susceptible to diseases and age-related decline like anemia, osteoporosis and decreased ability to repair bone fractures, decreased muscle repair, and decreased intestinal function.
Source: López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039
Altered Intercellular Communication
In addition to physical changes that occur inside of the cells, longevity research also suggests that aging affects the way cells communicate and maintain normal hormone signaling. The four proposed pathways that dysregulate normal signaling are:
- Neuroendocrine dysfunction—age-related imbalances in the body's hormone production directly related to the pituitary, hypothalamus, and their axes
- Immunosenescence—altered immune function characterized by diminished capacity to kill pathogens and clear defective cells (e.g., cancer cells)
- Inflammaging—a progressive pro-inflammatory state that increases inflammatory factors in the cells and surrounding tissues, disrupts autophagy, and inhibits normal cell function
- Bystander effects—senescent cells induce senescence in neighboring cells via cell to cell contacts and reactive oxygen species
What Can I Do to Minimize Cell Damage and Increase My Likelihood of Healthy Aging?
The relationship between these nine hallmarks and the aging process is by now well established in the scientific literature and the body of knowledge continues to grow at a rapid pace as more scientists are attracted by this field of research. A particular area of focus is in understanding how certain nutritional factors like vitamins and antioxidants, some drugs (e.g., metformin, rapamycin), and certain lifestyle factors can impact these pathways of cellular decline and help mitigate the damage that our bodies accumulate with age.
Here are some of the most popular intervention strategies found that have some solid grounding on scientific research:
- Vitamin A, C, and E—are powerful antioxidants that help protect our genomes from free radicals that cause damage.
- Omega-3—are polyunsaturated fats and serve as anti-inflammatory agents.
- CoQ10—is naturally produced by our bodies but decreases with age. Supplementation can help reduce cell damage caused by oxidative stress and free radicals.
- Curcumin—is the active compound in turmeric and activates sirtuins and AMP-activated protein kinase (AMPK) to decrease senescence.
- L-Theanine—is an amino acid found in green tea and can help prevent cognitive decline.
- Glutathione—is an antioxidant that prevents damage to cell machinery from exposure to free radicals and reactive O2.
- Epigallocatechin Gallate (EGCG)—is an antioxidant found in green tea and help restore mitochondrial function.
- Fisetin—is an antioxidant that has been shown to kill senescent cells in animal models.
- Resveratrol—is an antioxidant that activates sirtuins and protects cells from damage due to oxidative stress.
- Rapamycin—is an immunosuppressant drug that inhibits mTOR and has been shown to reverse age-related decline in animal models.
- Spermidine—is a compound found in living tissues and when supplemented has been shown to induce autophagy and may also reduce inflammation, improve lipid metabolism, and regulate cell growth.
- NAD+—is a compound critical for energy metabolism and DNA repair and declines with age. Supplementing NAD+ or it’s precursors NR and NMN can restore levels and prevent mitochondrial dysfunction.
- Metformin—is an anti-diabetic medication that has been shown to slow aging in animal models and reduce age-related neurodegenerative disease like Alzheimer’s and cancer in humans. The mechanism of action remains unclear.
- Exercise—boosts mitochondrial health and improves the density of skeletal muscle.
- Diet—diets that induce ketosis and the subsequent production of ketones as an energy source have been shown to slow aging in the brain. It is important to note that while your body can survive on ketones, they are not the preferred source of fuel and are only produced when your body is in a fasted state.
Regardless of your health status, it’s never too early (or too late) to understand the changes that take place as we age and incorporate strategies to minimize the damage done to your cells. The above interventions present little-to-no risk and have the potential to generate many health benefits. Are you ready to tackle the hallmarks of aging?
Check out these longevity gurus to learn more about what’s new in aging research
- Aubrey de Grey
- Ben Greenfield
- David Sinclair
- Rhonda Patrick
- Peter Attia–Check out his dive into a recently published efficacy trial of NMN (NAD+ precursor) here
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