Biomarkers of Aging


Scientists and medical professionals use the term "biomarker" to refer to a "subcategory of medical signs – that is, objective indications of medical state observed from outside the patient – which can be measured accurately and reproducibly."

Humans age differently from each other; therefore, chronological age does not provide an adequate marker of functionality and of the likelihood of age-related disease. By looking at biomarkers individually or integrating multiple biomarkers in a more complex analysis, we might be able to get a clearer picture of how a body is aging. Some have proposed that the best biomarker is the incidence of age-related diseases.

Criteria for Selecting a Biomarker of Aging

Suppose you wanted to know whether an activity (e.g. diet, exercise) or intervention (e.g. surgery, drug) has an effect on life expectancy or functionality in old age. The old fashioned way to do that was to observe the life of the subject until their death. If we can find biomarkers we can more quickly see the effect of interventions. These biomarkers can help in understanding if, for example, a drug can slow the aging process.

To ensure consistency, there should be a standard criterion that a biomarker for aging needs to meet. One organization that has defined such a criterion is the American Federation for Aging Research (AFAR). According to AFAR, a true biomarker is one that meets the following criteria:

  • "It must predict the future onset of age-related conditions and diseases, and do so independently of chronological age.
  • It must be testable and not harmful to test subjects…
  • It must also be technically simple so that most clinical laboratories could perform the test accurately and reproducibly...
  • It should work in laboratory animals as well as humans, since preliminary testing is always done in non-human subjects."

However, finding biomarkers that meet all the conditions set by AFAR is tough. Therefore, some researchers have focused on partially meeting the criteria. For example, in their study of biomarkers of aging, Xian Xia et al required the biomarker to be correlated with aging and to monitor the biological processes that underlie aging.

Molecular Biomarkers of Aging

Several molecular biomarkers of aging have been found, including telomeres, DNA repair, epigenetic modifications, nutrient sensing, protein metabolism and non-coding RNAs, among others. Here is an explanation of three of these biomarkers: telomeres, DNA repair and epigenetic modifications.

Telomeres

Telomeres are the protective ends of a chromosome. In technical terms, they are specific DNA–protein structures that "protect [the] genome from nucleolytic degradation, unnecessary recombination, repair, and interchromosomal fusion."(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370421/)

Telomere attrition suppresses cell proliferation and induces cellular senescence. Studies have shown that telomere shortening in bone tissue inhibits cell division and cellular function while its prolongation and maintenance prevents cellular senescence in osteosarcoma cells. Loss of telomere maintenance is therefore linked with the pathogenesis of musculoskeletal disorders such as osteoporosis, osteoarthritis, and osteosarcoma. Telomerase production declines with age hence the susceptibility of the elderly to musculoskeletal maladies.

Research has shown a connection between the length of telomeres in leukocytes and aging and age-related diseases. Moreover, longer and more active telomeres stabilize the genome, along with having a positive correlation with the lower rates of age-related disease.

DNA Repair

Genomic rearrangements and senescent cell accumulation are linked to DNA damage and repair. In terms of biomarkers, the immunohistochemistry of H2A protein called γ-H2A.X is a reliable biomarker for DNA damage because it "is an initial and essential component of DNA damage foci."

DNA repair capacity seems to be reduced in the elderly; this reduction is considered a consequence of aging. However, some research shows a negative correlation between the two after a certain point: Researchers found that chromosome-related damage increased linearly in the subjects from ages 60 to 70 years, but it decreased after the age of 85 years. Researchers also found that longer telomeres contribute to DNA integrity. Moreover, “DNA repair activity, and antioxidant defense capacity in successfully aged subjects is comparable to younger cohorts.” [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924179/]

Epigenetic Modifications

Distinct epigenetic alterations occur with aging, such as cystone methylation and histone mark variations, changes in nucleosome positioning and occupancy, loss of core histones, and increased histone variants. These modifications can be reprogrammed, reversing many age-related phenotypes, which might offer new ways for therapy of age-associated diseases, a safe approach to healthy aging, rejuvenation, and increased longevity.

DNA methylation patterns related to age is an extensively researched biomarker. DNA methylation is an epigenetic mechanism in which methyl (CH3) group is added to the DNA to modify gene functionality and expression.

DNA methylation is relevant to the concept of the epigenetic clock. The clock estimates chronological age based on DNA methylation levels of 353 dinucleotide markers called Cytosine phosphate Guanines (CpGs). The concept or model resulted from an analysis of “peripheral blood mononuclear cells isolated from semi-supercentenarians and their children.” Research shows that the there is an independent association between chronological age and mortality and the extent and patterns of CpGs.

Other research on blood methylation profiles shows that merely three CpG sites are predictors of age. The mean absolute deviation from chronological age was under 5 years.

The breakdown of epigenetic mechanisms contributes to genome instability. When epigenetic processes like DNA methylation are inefficient, embryogenesis, genomic imprinting, and chromosomal stability can be affected. Epigenetic errors can give rise to the expression of abnormal genes hence resulting in the synthesize of abnormal proteins. Accumulation of abnormal proteins impairs protein homeostasis, accelerating aging and the pathogenesis of neurodegenerative disorders as well as cancer.

Phenotypic Biomarkers of Aging

In practical terms, physical function and anthropometry are the most suitable phenotypic biomarkers. These biomarkers include body mass index (BMI), walking speed, standing balance, muscle mass, etc. When it comes to predicting health status, these physical functional measurements can perform better than DNA methylation.

Research also shows a notable relation between aging and quantitative phenotypes of external features of humans. There is a strong association between age and quantified facial features based on 3D images. In other words, people tend to look their age.

Ageotypes

Some researchers at Stanford University School of Medicine have added a new dimension to age measures by dividing humans into different classes that they call ageotypes. "We're able to see clear patterns of how individuals experience aging on a molecular level, and there's quite a bit of difference." stated Michael Snyder, PhD, senior author of the study and professor and chair of genetics. [Source: https://www.sciencedaily.com/releases/2020/01/200113111054.htm

The ageotypes include metabolic, immune, hepatic and nephrotic, and they indicate the paths in which the increases in biomarkers of aging are taking place most visibly.