Longevity Articles

Tick, Tock, Biological Clock: A Look at the Factors That Accelerate Internal Aging

many factors accelerate aging and our biological clocks

While you may consider aging to be determined by how many candles are on your birthday cake each year, researchers use a multitude of biological markers to indicate how quickly your cells, organs, and tissues are aging. As opposed to the chronological age that measures the number of years you’ve spent on earth, biological age assesses damage and dysfunction to cellular markers. And while these two tend to line up during our younger years, as we grow older, they can drift further and further apart. With an accelerated biological clock, you’re more likely to experience an earlier onset of age-related diseases, like dementia, heart disease, arthritis, or vision loss. On the flip side, maintaining healthy habits throughout life can keep you biologically young regardless of chronological age. However, researchers have yet to agree on the best way to measure the aging process. 

In a February 2021 study published in eLife, a collaborative team out of Amsterdam and Virginia aimed to determine the relationship between several biomarkers — also known as biological clocks — and whether a combined model using five major biomarkers could better predict biological age than any one marker on its own. As summarized by lead author Rick Jansen, "To develop a better understanding of the mechanisms underlying biological aging, we wanted to examine how indicators of biological aging relate to each other, how they link to determinants of physical and mental health, and whether a combined biological clock, made up of all age indicators is a better predictor of health.” With this study, Jansen and colleagues elucidate the differences between different markers of internal aging and underscore the importance of not relying on any one clock to determine biological age.

The big five: How is internal aging measured?

Although there are many ways to look at aging, these researchers looked at five different biological clocks that have previously been studied for their relationship to accelerated aging and disease: 

  • Telomere length: Telomeres are the endcaps on the tips of chromosomes, protecting them from damage and dysfunction. Telomeres shorten with each cell division in order to preserve critical genetic information; when a cell reaches the end of its telomere, it can no longer replicate and loses function. Shorter telomeres are consistently linked to shorter lifespans and an increased risk of chronic disease.
  • Epigenetics: Epigenetic age is measured by chemical changes to DNA. This includes DNA methylation — the addition of a methyl group to DNA — which doesn’t change the DNA sequence itself but, rather, leads to alterations in gene activity. As aging markedly increases the amount of methylated DNA, this epigenetic clock is often considered an excellent representation of biological age.
  • Transcriptomics: Changes to the transcriptome, or the full set of messenger RNA molecules that synthesize proteins from genetic material, are linked to biological aging. A loss of transcriptional regulation occurs with age, changing the blueprint for protein synthesis.
  • Metabolomics: This is the study of the metabolome — a group of small molecules involved with metabolism called metabolites. Age-related changes to the metabolome can include reductions in the vital coenzyme NAD+ and increases in inflammatory metabolites. 
  • Proteomics: Proteomics looks at the proteome, or the entire compilation of proteins in the body. With age, the proper synthesis, folding, and regulation of proteins deteriorates. 

While these five markers measure different biological mechanisms in the body, they all are altered or dysregulated with age. Most studies look at just one or two of them; however, it’s unlikely that a single biological clock can fully capture the aging process.

So, Jansen and colleagues looked at how these biomarkers interact with each other in a cohort of approximately 3,000 adults from the Netherlands Study of Depression and Anxiety. Although not all the participants had measurements from all of the biological clocks — just 653 people had all five — the data provided a new insight into how individual factors influence these markers of aging, from demographics to lifestyle choices to physical and mental health. 

DNA damage can accelerate biological aging

What makes these biological clocks tick faster?

For each of the five biological clocks, the research team computed the associations between these markers and about a dozen determinants of health — such as sex, smoking status, and physical activity levels, to name a few. The strongest associations were found between sex and biological age, as men were found to be biologically older than the women in this study. With the exception of proteomic age, males had greater ages on the other four biological clocks. Other lifestyle-related links included alcohol use, which advanced proteomic age, and smoking cigarettes, which led to shorter telomeres and increased transcriptomic, proteomic, and metabolomic aging. 

In terms of physical health, higher BMI (Body Mass Index) was strongly correlated to increased biological age among all five markers. Chronic disease states were unsurprisingly linked to increased biological age. Specifically, endocrine diseases (including diabetes) were tied to advanced proteomic aging, and metabolic syndrome — the cluster of conditions that includes high blood pressure and sugar, obesity, and abnormal cholesterol and lipid levels — advanced aging related to all of the clocks except epigenetic. Lastly, and somewhat surprisingly, chronic depression was significantly linked to increased epigenetic and proteomic aging, highlighting the previously unconfirmed link between mental health disorders and aging. However, the overall correlations and overlap between the five biological aging clocks were small, indicating that measuring just one of these aging indicators may not be sufficient to quantify biological age.

Next, Jansen and colleagues created an algorithm that combined the data from the 653 participants with all five biomarkers into a composite score of biological aging. In this combined biological clock, more significant correlations were seen. The most robust associations between biological aging and health determinants were being of male sex, smoking, and having a high BMI, chronic depression, or metabolic syndrome. Additionally, this composite score uncovered an association between childhood trauma exposure and higher biological age, further strengthening the idea that mental health impacts aging. These weightier associations on the combined biological score suggest that using more than one — ideally all five — biomarkers can better predict how fast someone is aging internally. 

Future targets: Slowing down the clock

Although some of these factors, like being born of male sex and having childhood trauma, cannot be changed, others can be altered to slow down biological aging, including maintaining a healthy body weight and blood sugar and not smoking. While it’s known that chronic diseases like diabetes and metabolic syndrome accelerate aging, less attention has been paid to aging’s relationship with mental health disorders, suggesting mental health support as a new potential target to slow aging. “Taken together, our findings contribute to the understanding and identification of biological age determinants, important to the development of endpoints for clinical and epidemiological research,” the authors conclude. The more we know about defining and quantifying aging on a cellular level, the more doors open to prevent, treat, or reverse it.


Jansen R, Han LK, Verhoeven JE, et al. An integrative study of five biological clocks in somatic and mental health. Elife. 2021;10:e59479. Published 2021 Feb 9. doi:10.7554/eLife.59479

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