Biological age indices
The marker of arterial health can serve as an accurate non-invasive indicator of a person's biological and chronological age
An individual approach to optimal, rather than "normal" or "typical" health provides an opportunity to determine the biological age and aging rate of each individual.
Throughout our lives, each of us gradually moves away from the trajectory of health determined by our personal genome. At later stages of ontogenesis, non-genetic factors, both exogenous and endogenous, become important, which means that the rate of aging of an adult depends primarily on lifestyle, and not on genes. It is hoped that anti-aging interventions will allow people to actively counteract aging and pharmacologically correct accumulating deficits, both biochemical and functional. Objective indicators reflecting the rate of aging are needed to correctly assess the relative effectiveness of various interventions.
The search for a better definition of biological age began in 1969, with the seminal article Comfort. The chronological age of a person is not difficult to determine, since you can always look at the birth certificate, while the mission of determining the biological age without such a record is still not feasible. At best, biological age can be reflected as the degree of similarity of an elderly person with the average amount of age-related changes observed in a given population in individuals of a particular age. Within this definition, any deviation from the generally accepted standard of aging is due to a combination of environmental and genetic factors that contribute to or delay the development and subsequent involution of various physiological systems and a decrease in their ability to adapt. The positive or negative difference between biological and chronological age observed in a given individual can be interpreted as an acceleration or deceleration of aging. Ideally, objective biomarkers of aging can be used to evaluate new anti-aging tools.
The history of attempts to determine biological age and quantify the pace of the aging process is very extensive. As a rule, the determination of age is based on one or another molecular aspect of aging, for example, the degree of damage to the DNA of a cell. Among the newly developed integrative biomarkers of aging is the GlycanAge index, based on the assessment of the structural details of sugar chains attached to specific sites of three types of IgG molecules. This indicator reflects the level of systemic inflammation, predicts chronological age with a standard deviation of 9.7 years and exceeds the accuracy of the age estimate using telomere length. Based on the analysis of mRNA of peripheral blood mononuclear cells (RVMS), the "transcriptomic age" index predicts chronological age with an average absolute error of 7.8 years. An even more accurate "epigenetic age" is based on determining the amount of methylation of three CpG sites located in the ITGA2B, ASPA and PDE4C genes with a standard deviation of less than 5 years. Increasing the number of CpG-profiled dinucleotides to 353 improves estimates based on epigenetics, reducing the margin of error to 2.9 years. This method is also able to predict overall mortality (p<0.003), but not the likelihood of serious cardiovascular events. It should be noted that all the methods described above require specialized equipment and qualified laboratory personnel, which limits their clinical applicability.
At the other end of the spectrum, age prediction models are presented that are not related to any specific aging mechanism, for example, deep learning neural network modules (DNNs) that evaluate general biochemical parameters and tests based on counting the number of different types of colvi cells. Although the accuracy of this model is quite high, the number of parameters in the model is also large. Since deep neural networks, in a nutshell, are "black boxes", it is simply impossible to understand the models obtained in this way in detail and to understand something about the mechanisms of aging with their help.
Most of the methods described above have not yet entered clinical practice. The main culprits of this are parameters that require evaluation. Simply put, there are too many of them. In addition, the tests described above are laboratory, not clinical, so they cannot be performed in a district polyclinic.
From a clinical point of view, the most convenient assessment of biological age is some kind of "advanced" analysis of biochemical and physiological parameters, which in one way or another are already evaluated by a doctor during an annual physical examination.
Recently, articles have been published describing a number of attempts to derive the value of biological age from readily available clinical parameters, including those developed using large cohorts of the US population of NHANES, young people from Dunedin, the Long Life Family Study or combinations thereof. Interestingly, a number of studies have shown that aging is accompanied by the development of complex physiological disorders affecting several body systems at once, but at the same time, no physiological system becomes an obvious source of "signaling" biomarkers that accurately reflect the rate of aging of the entire organism.
The study, which we will tell you about, was carried out with the participation of 303 subjects of various ages. 89 clinical and biochemical parameters were measured for each study participant, then five parameters with the highest correlation with chronological age were selected (Pearson correlation was used), while it turned out that all the selected parameters ultimately reflect the functioning of the cardiovascular system. The results of gender-oriented linear regression models predicting chronological age were compared with the actual age of the subjects. The highest differences between the predicted age and calendar age, and not for the better, were noted in patients with type 2 diabetes mellitus.
The proposed gender-oriented models were called Male and Female Arterial Indices. These indexes are able to estimate the elusive biological age with a good approximation.
It is important to note that the proposed methods of age approximation are based on functional tests that do not require specialized laboratory equipment and, therefore, can be performed in non-specialized hospitals and polyclinic medical institutions at the place of residence, without the need for molecular or cellular tests.
Arterial indicators for calculating Indices are evaluated noninvasively, by quantifying four functional indicators of cardiovascular health, using a combination of duplex scanning of the carotid artery and planar tonometry.
Cardiovascular diseases are a major component of age-related mortality. Aging is associated with functional changes in blood vessels, including an increase in arterial stiffness, which is the main factor of hypertension. Moreover, a recent publication has shown that arterial aging correlates with chronological age much more strongly than concomitant changes in blood biochemistry.
Intima-media thickness of the carotid artery (cIMT) is an established surrogate marker of atherosclerosis. This parameter is also associated with metabolic syndrome, insulin sensitivity and other age-related functional disorders. In addition, it has been shown that the thickness of intimate media reliably predicts the progression of Alzheimer's disease in general and Alzheimer's-related cognitive decline in particular. Moreover, revascularization improves cognitive function, which indicates a connection between carotid artery stenosis and cognitive depression.
Another cardiovascular predictor, the Pulse Wave Rate Increase Index (AIx), is an indication of the likelihood of cardiovascular events and mortality from any cause
A recent study showed that arterial age, which is expressed as the degree of calcification of the coronary arteries, predicts an increased risk of cancer, chronic obstructive pulmonary disease, chronic kidney disease and hip fractures. Increased arterial stiffness affects the supply of oxygen and nutrients to tissues. Thus, the process of arterial aging can be considered as a key factor in the overall aging process.
It is noteworthy that the individual components of the Arterial Index predicting age are amenable to improvement due to lifestyle, nutrition or medications. Thus, it has been shown that the geroprotective compound acarbose, which reduces glucose levels, lowers arterial stiffness by suppressing the levels of proinflammatory and profibrotic mediators CRP, PTX3, MMP-2 and MMP-9 in blood plasma. The pulse rate can be improved by increasing the intake of glutamic acid, leucine and tyrosine, as well as a low dose of valsartan either alone or in combination with fluvastatin, or – in mice – with spermidine supplements.
Patients with more than five years of "additional aging", that is, individuals with high arterial index scores, also had high Framingham risk prognosis for the cardiovascular system and low serum IGF-1 levels, which is the main factor affecting the level of growth hormone (GH).
The proposed Arterial Indices can be useful for predicting biological age, while the deviation of these predictions from chronological age can be considered as an indicator of an increase in arterial and, probably, the overall rate of aging. Arterial Indices can be used either independently or in combination with other biomarkers of elusive biological age and serve as surrogate results for studies of the effectiveness of interventions in the fight against aging.
Article by Fedintsev et al. Markers of arterial health could serve as accurate non-invasive predictors of human biological and chronological age published in the journal Aging.
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29.05.2017