Biological vs. Chronological Aging

Aging is one of those simple facts of life – it affects us all. It is marked by the inevitable decline in physiological function and an increased risk of disease... and lots of wrinkles, unless you live in South Korea, the plastic surgery capital of the world [1,2].

There are, however, some very distinct differences between chronological aging (your age in terms of years) and biological aging. In this article, we will explore the nuances and details of these types of aging. We will also discuss some of the methods in which we can measure the differences between the two. 

The Different Types of Aging 

As mentioned above, chronological aging is simply the amount of time that a person has been alive (the number of years that have elapsed from birth to a given date), and is the main way that we characterize age [3].

Biological aging (sometimes called physiological or functional age) takes place over time as a person gradually accumulates damage to the cells of the body [3]. 

In this way, biological aging doesn’t just take into account the passage of time in years, but also the different physiological factors involved, such as diet, lifestyle, genetics, nutrition, and disease (i.e., inflammation) [3,4]. 

Although chronological age is correlated with various age-related diseases and other conditions, it does not appropriately indicate a person’s functional capacity, well-being, or risk of death (mortality) [5]. Biological aging provides this information. 

How Can We Quantify Biological Age? All About Aging Clocks 

Aging clocks specifically aim to inform people about their biological age, and can be devised from any biological system (i.e., humans) with features that change during aging. Many aging clocks exist, with some using blood biomarkers, epigenetic mechanisms, extracellular vesicles, telomere length, grip strength, and so on [6]. A selection of these clocks will be discussed in further detail in this article.

An epigenetic clock is a biochemical test that measures age, predominantly by assessing the DNA methylation levels (the accumulation of methyl groups on a person’s DNA). DNA methylation is suspected to play a role in regulating lifespan, and serves as an important epigenetic marker involved in many diverse processes within the cell [7].

These clocks are computational models that bring together a series of different inputs (e.g., DNA methylation sites) to make predictions about biological age [5]. Although they were initially geared towards estimating chronological age, they have evolved to serve as indicators of lifespan and healthspan [1]. 

Over the past ten years, studies of these "aging clocks" have found that several age-related diseases, social variables, and mental health conditions all associate with an increase in predicted biological age relative to chronological age [5]. 

The discrepancy between the DNA methylation age and chronological age can be used to determine a measure of age acceleration. Age acceleration is therefore the difference between DNA methylation age and chronological age. If age acceleration is positive, it suggests that the underlying tissue and biology is aging at a faster rate than expected, and the opposite is true should age acceleration be negative.

One of the more famous aging clocks is the DNAmAge clock developed by Professor Steve Horvath. This is a multi-tissue predictor of age that allows the estimation of DNA methylation age across most tissues and cell types [8]. Other notable clocks that Horvath and others have developed include the skin and blood clock and the GrimAge clock. The former uses skin and blood to predict lifespan and relates to many age-associated conditions [9,10]. The latter is a second-generation clock that was designed to overcome the limitations of prior clocks, namely by including DNA methylation which correlates morbidity and mortality. It has been heralded as a biomarker of aging with substantial promise over other epigenetic clocks [11].

Other Aging Clocks

Next-generation clocks are emerging that utilize proteomics instead of methylation biology – that is, they use measures of circulating proteins to construct the biomarker clock instead, and these clocks have been highly correlated with chronological age [12].

In a similar vein, other clocks have used advanced glycation end products (AGEs) as the aging biomarker [13]. For example, sRAGE is a soluble form of RAGE (receptor of advanced glycation end products) that circulates in the blood [13]. In women, higher levels of AGEs and the ratio of AGE/sRAGE were associated with lower physical functioning even after accounting for lifestyle and age-related factors such as education, diet, and disease state [13]. 

What Detrimentally Affects the "Aging Clock"? 

New research in a Costa Rican cohort has shown that cigarette smoking is associated with DNA methylation signatures and increased GrimAge (2.34 years), suggesting epigenetic age acceleration [14]. In fact, cigarette smoking seems to be one of the worst things to do to epigenetic aging. Obesity, high blood pressure, psychiatric disease, and many other factors also significantly impact GrimAge clocks! Psychedelics reverse all of these. Okay, just kidding. But maybe...?

Can We Slow or Reverse the "Aging Clock"? 

Human studies report that caloric restriction (reducing the amount of energy consumed from food) [15], lifestyle changes involving exercise, a drug regime including metformin, and supplementation with vitamin D can all help slow down or reverse an aging clock [5]. 

For example, a recent randomized clinical trial found that an 8-week trial involving diet, sleep, exercise and relaxation guidance, as well as supplemental probiotics and phytonutrients improved DNAmAge (by around 1.96 years) as per the Horvath clock [16]. DNA methylation analysis was carried out on saliva samples from 43 participants between 50-72 years of age, and the trial concluded that so-called "epigenetic aging" can be reduced by diet and lifestyle interventions. 

In addition to these studies, non-interventional research has found that obtaining high quality sleep, getting enough physical activity, a healthy diet, and other factors might also be linked to age deceleration. 

The work of Dr. David Sinclair, a renowned expert in the biology and slowing of aging, has explored the therapeutic potential of many different compounds. One is nicotinamide adenine dinucleotide (NAD), the cell’s hydrogen carrier for redox enzymes. It is involved in literally hundreds of reactions and processes linked to energy metabolism, cell survival, and more [17]. With age, NAD+ levels decline, causing an increased likelihood of disease and altered metabolism. By the time we get to older age, our NAD+ levels have dropped to half that seen in our youth [18]. Dr. Sinclair’s work has attempted to understand how using NAD-boosting molecules can help promote health and extend the lifespan.

Dr. Sinclair and his team have also famously investigated the role of sirtuins in slowing the aging process. Sirtuins are a family of signaling proteins that are conserved across all domains of life and are involved in all manner of processes including aging, gene transcription, apoptosis, and inflammation, to name a few [19]. Though the sirtuins are closely intertwined with NAD+, SIRT1 through to SIRT7 have all demonstrated an ability to prevent disease and even reverse aspects of aging [20]. 

Lastly, Dr. Sinclair’s work has also investigated the potential use of resveratrol (a natural phenol found in the skin of grapes, blueberries, and raspberries, to name a few) as a SIRT1 activator that might confer anti-aging benefits for humans [21]. It has also explored the utility of metformin (a medication more widely known to control type II diabetes) as a candidate for extending lifespan and healthspan [22,23].

Are Tests for Biological Aging Available? 

Several companies are offering tests using aging clocks. TruDiagnostic is one such company that has state-of-the-art epigenetic testing facilities and uses DNA methylation techniques to accurately profile aging. Another company, GlycanAge, uses blood tests to profile the age of the immune system, which can then be used as a predictor of biological age. Lastly, myDNAge is a service that uses an epigenetic age determination test that makes use of Horvath’s clock discussed earlier, based on the understanding of DNA methylation and its relationship with biological age.

Conclusion

Age, indeed is just a number, and although we can't reverse chronological age yet (Benjamin Button, we are looking at you), there are many ways we can potentially reverse biological age. In the next decade, biological age testing will get more accurate as well. For now, Dr. Ted, the Chief Daydreamer and Founder of Troscriptions, will settle for being chronologically 60, telomerically 32, and epigenetically 22.5. What will you settle for? This is under more control than we realize! 

References

[1]        R. Noroozi, S. Ghafouri-Fard, A. Pisarek, J. Rudnicka, M. Spólnicka, W. Branicki, M. Taheri, E. Pośpiech, DNA methylation-based age clocks: From age prediction to age reversion, Ageing Res Rev. 68 (2021) 101314. https://doi.org/10.1016/j.arr.2021.101314. 

[2]        A.E. Kane, D.A. Sinclair, Epigenetic changes during aging and their reprogramming potential, Crit Rev Biochem Mol Biol. 54 (2019) 61–83. https://doi.org/10.1080/10409238.2019.1570075. 

[3]        R. Maltoni, S. Ravaioli, G. Bronte, M. Mazza, C. Cerchione, I. Massa, W. Balzi, M. Cortesi, M. Zanoni, S. Bravaccini, Chronological age or biological age: What drives the choice of adjuvant treatment in elderly breast cancer patients?, Transl Oncol. 15 (2022) 101300. https://doi.org/10.1016/j.tranon.2021.101300. 

[4]        S.M. Jazwinski, S. Kim, Examination of the Dimensions of Biological Age, Front Genet. 10 (2019) 263. https://doi.org/10.3389/fgene.2019.00263. 

[5]        A.A. Johnson, B.W. English, M.N. Shokhirev, D.A. Sinclair, T.L. Cuellar, Human age reversal: Fact or fiction?, Aging Cell. 21 (2022) e13664. https://doi.org/10.1111/acel.13664. 

[6]        R.D. Palmer, Aging clocks & mortality timers, methylation, glycomic, telomeric and more. A window to measuring biological age, Aging Med (Milton). 5 (2022) 120–125. https://doi.org/10.1002/agm2.12197. 

[7]        I. Rauluseviciute, F. Drabløs, M.B. Rye, DNA methylation data by sequencing: experimental approaches and recommendations for tools and pipelines for data analysis, Clin Epigenet. 11 (2019) 193. https://doi.org/10.1186/s13148-019-0795-x. 

[8]        S. Horvath, DNA methylation age of human tissues and cell types, Genome Biol. 14 (2013) R115. https://doi.org/10.1186/gb-2013-14-10-r115. 

[9]        S. Horvath, J. Oshima, G.M. Martin, A.T. Lu, A. Quach, H. Cohen, S. Felton, M. Matsuyama, D. Lowe, S. Kabacik, J.G. Wilson, A.P. Reiner, A. Maierhofer, J. Flunkert, A. Aviv, L. Hou, A.A. Baccarelli, Y. Li, J.D. Stewart, E.A. Whitsel, L. Ferrucci, S. Matsuyama, K. Raj, Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies, Aging. 10 (2018) 1758–1775. https://doi.org/10.18632/aging.101508. 

[10]      G. Hannum, J. Guinney, L. Zhao, L. Zhang, G. Hughes, S. Sadda, B. Klotzle, M. Bibikova, J.-B. Fan, Y. Gao, R. Deconde, M. Chen, I. Rajapakse, S. Friend, T. Ideker, K. Zhang, Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates, Molecular Cell. 49 (2013) 359–367. https://doi.org/10.1016/j.molcel.2012.10.016. 

[11]      C. McCrory, G. Fiorito, B. Hernandez, S. Polidoro, A.M. O’Halloran, A. Hever, C. Ni Cheallaigh, A.T. Lu, S. Horvath, P. Vineis, R.A. Kenny, GrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause Mortality, The Journals of Gerontology: Series A. 76 (2021) 741–749. https://doi.org/10.1093/gerona/glaa286. 

[12]      L. Ferrucci, T. Tanaka, A PROTEOMIC CLOCK OF AGING, Innovation in Aging. 2 (2018) 62–62. https://doi.org/10.1093/geroni/igy023.233. 

[13]      H. Ebert, M.E. Lacruz, A. Kluttig, A. Simm, K.H. Greiser, D. Tiller, N. Kartschmit, R. Mikolajczyk, Advanced glycation end products and their ratio to soluble receptor are associated with limitations in physical functioning only in women: results from the CARLA cohort, BMC Geriatr. 19 (2019) 299. https://doi.org/10.1186/s12877-019-1323-8. 

[14]      A. Cardenas, S. Ecker, R.P. Fadadu, K. Huen, A. Orozco, L.M. McEwen, H.-R. Engelbrecht, N. Gladish, M.S. Kobor, L. Rosero-Bixby, W.H. Dow, D.H. Rehkopf, Epigenome-wide association study and epigenetic age acceleration associated with cigarette smoking among Costa Rican adults, Sci Rep. 12 (2022) 4277. https://doi.org/10.1038/s41598-022-08160-w. 

[15]      D.A. Sinclair, Toward a unified theory of caloric restriction and longevity regulation, Mech Ageing Dev. 126 (2005) 987–1002. https://doi.org/10.1016/j.mad.2005.03.019. 

[16]      K.N. Fitzgerald, R. Hodges, D. Hanes, E. Stack, D. Cheishvili, M. Szyf, J. Henkel, M.W. Twedt, D. Giannopoulou, J. Herdell, S. Logan, R. Bradley, Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial, Aging (Albany NY). 13 (2021) 9419–9432. https://doi.org/10.18632/aging.202913. 

[17]      L. Rajman, K. Chwalek, D.A. Sinclair, Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence, Cell Metab. 27 (2018) 529–547. https://doi.org/10.1016/j.cmet.2018.02.011. 

[18]      X.-H. Zhu, M. Lu, B.-Y. Lee, K. Ugurbil, W. Chen, In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences, Proc Natl Acad Sci U S A. 112 (2015) 2876–2881. https://doi.org/10.1073/pnas.1417921112. 

[19]      R.H. Houtkooper, E. Pirinen, J. Auwerx, Sirtuins as regulators of metabolism and healthspan, Nat Rev Mol Cell Biol. 13 (2012) 225–238. https://doi.org/10.1038/nrm3293. 

[20]      M.S. Bonkowski, D.A. Sinclair, Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds, Nat Rev Mol Cell Biol. 17 (2016) 679–690. https://doi.org/10.1038/nrm.2016.93. 

[21]      B.P. Hubbard, D.A. Sinclair, Small molecule SIRT1 activators for the treatment of aging and age-related diseases, Trends Pharmacol Sci. 35 (2014) 146–154. https://doi.org/10.1016/j.tips.2013.12.004. 

[22]      A. Martin-Montalvo, E.M. Mercken, S.J. Mitchell, H.H. Palacios, P.L. Mote, M. Scheibye-Knudsen, A.P. Gomes, T.M. Ward, R.K. Minor, M.-J. Blouin, M. Schwab, M. Pollak, Y. Zhang, Y. Yu, K.G. Becker, V.A. Bohr, D.K. Ingram, D.A. Sinclair, N.S. Wolf, S.R. Spindler, M. Bernier, R. de Cabo, Metformin improves healthspan and lifespan in mice, Nat Commun. 4 (2013) 2192. https://doi.org/10.1038/ncomms3192. 

[23]      I. Mohammed, M.D. Hollenberg, H. Ding, C.R. Triggle, A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan, Front. Endocrinol. 12 (2021) 718942. https://doi.org/10.3389/fendo.2021.718942.