Secrets of Aging

In this guest blog for Lab Crunches, Shermaine Thein explores the concept of aging and why how old we are may not be as simple as just a number.

Supercentenarians: Tales of Exceptional Longevity

Jeanne Calment is currently the world’s oldest recorded person, living to 122 years old. Depicted as a petite lady of irrepressible wit and exuberance, it’s hard to imagine that she experienced life at the turn of the century; living through key events that shaped our history. In interviews, it was revealed that she’s even met the famed recluse painter, Vincent Van Gogh! Jeanne retained her dynamism despite her advancing age, having famously peddled around her hometown of Arles, France on her bicycle till the age of 100 (Smyth 2018).

Like Jeanne, the Japanese sprinter Hidekichi Miyazaki’s astounded his physicians with his achievement in completing the 100 m sprint in the Kyoto Master’s competition. He was 105 years old, earning him the moniker ‘Golden Bolt’ and a world record (McCurry 2015).

Jeanne and Hidekichi are some of the individuals referred to as centenarians (or in extreme cases, supercentenarians). Unlike the majority of their peers, they live exceptionally long lives and are often prime examples when one considers the notion of ‘successful aging’. As of 2021, a United Nations report estimates that there are 573,000 centenarians in the world (United Nations, 2021). In fact, there are five communities around the world including Okinawa, Japan and Ikaria, Greece, with the highest concentration of centenarians (Buettner 2021).

The presence of centenarians prompts eternal questions surrounding aging and mortality. What is the mysterious secret to longevity, often accompanied by good health and activity compared to their peers? Another stark revelation is that we are probably not aging at the same pace; the rate of aging is heterogeneous between individuals. If this is true, how can we properly measure what our “true” rate of aging actually is?

What’s Your Age, Really?

In aging research, there are two distinct ways to measure aging; chronological and biological aging. We are probably all well-acquainted with the traditional concept of chronological age; representing the amount of time that has elapsed since our birth, people born on the same day would invariably share the same chronological age throughout life. Their biological age, however, may tell a drastically different tale.

As opposed to its predecessor, biological age is proposed to be a more ideal measure of one’s aging process (Baker and Sprott 1988). While chronological age is time-centric, biological age emphasizes the age-associated changes in function, and the pivotal biological process that govern these changes (Warner 2004). In a nutshell, it looks at how your organs, tissues, and cells are actually aging.

As in the case of centenarians who seem impervious to their chronological age, it is unsurprising then, that both biological and chronological ages can be very diverse.

The Search for Biomarkers of Aging

Despite being an ideal standard of measuring aging, the road to finding biomarkers which accurately predict biological age has not been a straightforward one. Owing to the intrinsically complex nature of the aging process itself, consensus surrounding aging biomarkers has yet to be reached (Partridge et al. 2018). Initial guidelines to streamline prospective biomarkers proved to be notoriously hard to achieve, with early candidates not being suitably robust in predicting biological aging (Lara et al. 2015).

Nonetheless, the field has soldiered forward. Guided by the well-established hallmarks of aging, new emerging areas of biomarkers include assessment of mitochondrial function, autophagy, DNA repair capacity, telomere length, and quantifying senescence (Lopez-Otin et al. 2013, Xia et al. 2017). Much effort has been invested in refining each domain, with some showing great translational potential. For instance, independent groups have developed assays to detect senescent cells in biological materials, such as skin and T cells, while standard methodologies have been established to determine autophagy in both yeast and humans (Evangelou et al. 2016, Klionsky et al. 2007).

Tick Tock: the Epigenome and DNA Methylation Clocks

Of the biomarkers being developed, aging epigenetics is a specialty garnering immense interest (Ferrucci et al. 2020). Our genomic DNA holds a myriad of genetic instructions to keep our body functioning properly. In addition to this, added chemical changes can occur in our DNA throughout life, spurred on by external stimuli such as exercise or even dietary choices (Kanherkar et al. 2014). Though these changes leave the core DNA sequence unchanged, they often elicit changes in the “instructions” the DNA is conferring, altering gene function. Three major modifications in epigenetics are well-studied, histone modifications, noncoding RNA, and DNA methylation (Zhang et al. 2020).

In particular, earlier studies have demonstrated strong correlations between DNA methylation (DNAm) and chronological aging (Fraga and Esteller 2007). This finding led to the innovative discovery of “epigenetic clocks”; algorithms that could accurately estimate chronological age based on DNAm. The eponymously termed Horvath and Hannum clocks were pioneer clocks able to accomplish this feat (Hannum et al. 2013, Horvath 2013). Interestingly, recent research has suggested that differences between a person’s chronological age and DNAm calculated by these clocks can provide insight into one’s true biological age! For example, if an individual possessed an older methylation age than their chronological one, it could signal a faster rate of biological aging (Field et al. 2019). Supporting this, analysis of DNA methylation profiles in super-centenarians and their children show that they possess a remarkably younger epigenetic age compared to their actual age (as much as 8 years) (Horvath et al. 2015). Conversely, the Hannum clock revealed that an accelerated DNAm age of 5 years, in respect to chronological age, is associated with a higher risk of mortality (Marioni et al. 2015).

These findings have fueled excitement at the prospect of using DNAm as a solid biomarker of biological age. In 2018, a new clock was introduced by Levine et al. Clinical biomarkers, such as serum glucose and albumin levels, were also considered during the development of their algorithm, producing a more robust estimator of biological age (DNAm PhenoAge) rather than chronological age (Levine et al. 2018). DNAm PhenoAge was successfully tested against numerous age-related outcomes and across tissues such as liver, lung, and kidney. Impressively, DNAm PhenoAge was highly effective in predicting outcomes associated with aging, such as all-cause mortality, risk of coronary heart disease, and physical function (Levine et al. 2018).

These findings give a small glimpse of how future predictors of biological aging could be beneficial, both in basic and clinical aspects of research. This is undoubtedly preliminary, but it will be exciting to see how these new clocks will pivot the field of biomarker aging. Though the search so far has been fraught with complexities, each small discovery takes us a step closer to the ultimate goal of understanding how and why we age.