The way we understand aging is changing. Previously it was believed to be due to cumulative wear and tear that happened over decades, as seen in the thinning cartilage between joints. Recently research has suggested that aging is more likely to be a program of orderly self-destruction which is dictated by our genes. We used to believe that the buildup of oxidative damage and the cumulative toll of DNA mutations could explain the deterioration of our bodies over time. We now understand that aging is more likely due to the failure of our own DNA repair systems.
An influential review article in 2013 posited that there are nine hallmarks of aging (Lopez-Otin 2013):
- genomic instability,
- telomere attrition,
- epigenetic alterations,
- loss of protein homeostasis,
- deregulated nutrient sensing,
- mitochondrial dysfunction,
- cellular senescence,
- stem cell exhaustion and finally,
- altered intercellular communication (an example is chronic inflammation seen in aging).
Consequently, researchers have been trying to discover ways to slow or reverse aging by counteracting one or more of these interconnected body processes. For example, medications such as metformin and rapamycin have been advocated as ways to slow aging, primarily based on animal models.
Unfortunately, chemical remedies such as these often have potential side effects, and there is a lack of long-term safety data to advocate for these methods. Personally, I believe that regular strenuous exercise and caloric restriction are the safest and most evidence-based methods to increase the length of your healthy lifespan, also known as “healthspan”. Caloric restriction can be accomplished by time restricted eating, intermittent fasting or long-term reduction in daily caloric intake.
Let’s talk more about the hallmarks of aging. Four of the nine processes are primary causes of damage: instability of the genome, shortening of telomeres, epigenetic modifications and loss of protein homeostasis.
Every human being has approximately 20,000 genes. A gene is a sequence of DNA that codes for a protein which your body needs to function. DNA is made of four small proteins or nucleotides including adenine (A), guanine (G), cytosine (C) and thymine (T). These DNA sequences are tightly wrapped into structures called chromosomes. Our genes constantly encounter chemicals which may modify or change their nucleotide sequence. In addition, mutations may occur when genes are replicating. Over a lifetime, we see an accumulation of genetic damage from causes inside and outside the body.
Shortening of telomeres is also a common sign of aging genetic material. Our chromosomes are capped by telomeres which act like the plastic tips of shoelaces to protect the fidelity of the chromosome or “shoelace”. Telomeres also prevent the ends of separate chromosomes from fusing together. With each replication of DNA our telomeres get shorter and our DNA becomes more susceptible to damage. The term “Hayflick limit” (Hayflick and Moorhead 1961) describes the finite number of times cells in culture could divide before their protective telomeres were exhausted.
Epigenetic modifications are also important drivers of aging. Whereas genetic mutations are permanent, epigenetic modifications occurring throughout life are often reversible. Examples of epigenetic modifications include the addition of a methyl group (a molecule containing a carbon and three hydrogen atoms) to a specific gene. The methylation process can make a gene more or less susceptible to stimuli in the environment. A specific pattern of DNA methylation is appreciated during the aging process. Scientists have been able to look at the methylation pattern of specific genes to determine the age of an organism very accurately. This is known as an epigenetic clock (Horvath 2013).
Finally, the body’s decreasing ability to maintain properly functioning proteins (this also known as loss of proteostasis), is a primary cause of aging. To function well, the body relies on many different proteins. These proteins must be assembled and folded in a certain way. With age, proteins may become misfolded, unfolded or may start to accumulate in inappropriate areas. Age related diseases such as Alzheimer’s disease, Parkinson’s disease and cataracts are caused by loss of proteostasis. In the brain of an Alzheimer’s patient, one inevitably sees abnormal accumulations of beta-amyloid and tau proteins (forming amyloid plaques and neurofibrillary tangles).
When the damage due to these primary causes accumulates to a certain point, the body is no longer able to compensate effectively. That is when we start to see senescence of cells, chronic low-level inflammation and stem cell exhaustion.
Senescent cells are damaged cells which are no longer able to replicate. As we age the proportion of senescent cells in our body increases. In addition, stem cells in body tissues such as the blood, muscle and bone become less able to regenerate healthy tissue as we get older.
Finally, the term “inflammaging” describes the chronic low-level inflammation throughout the aging body that develops in the absence of infection. This is due to a failure of our innate disease-fighting immune system to function properly.
It’s important to remember that these hallmarks of aging are all interconnected and serve only as a conceptual framework for the aging process. Hopefully, we will continue to uncover more about the biology of aging and potential treatments as more research is done.
References
1. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. Cell, 153(6), 1194–1217. doi: 10.1016/j.cell.2013.05.039 https://www.cell.com/fulltext/S0092-8674(13)00645-4
2. Hayflick, L., & Moorhead, P. (1961). The serial cultivation of human diploid cell strains. Experimental Cell Research, 25(3), 585–621. doi: 10.1016/0014-4827(61)90192-6
3. Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology, 14(10). doi: 10.1186/gb-2013-14-10-r115 https://genomebiology.biomedcentral.com/articles/10.1186/gb-2013-14-10-r115