Measuring biological aging in humans: A quest

Abstract

The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well-established clinical guidelines. Physicians are often forced to engage in cycles of "trial and error" that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are "aging faster" to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

Keywords: aging; biological aging; hallmarks of aging; inflammation; multimorbidity; resilience; senescence.

Figure 1

Normal aging (a) and different pathways to accelerated aging (b and c). A. Robust resilience at a young age fully compensates damage. Over time, damage accumulates that is not fully compensated by resilience. Toward the end of life, resiliency is overwhelmed, and new stresses cause fast, unopposed damage accumulation that leads to frailty and eventually to death. Accelerated aging may occur either because of faster rates of damage accumulation (b) or because of rapid shrinking and eventual collapse of resilience (c). Note that even in the state of robustness, damage can be already abnormally high (b) and resilience already abnormally low (c)

Figure 2

Epigenetic model of continuous transcriptional tuning leading to the aging phenotype. Long‐term adaptation within the lifespan requires epigenetic modulation of the transcriptional machinery. Environmental clues are read by specific biosensors and encoded into epigenetic changes that modulate transcriptional subroutines. The new epigenetic landscape is meant to be adaptive but may fail its purpose and become maladaptive in either the short or long term. Ineffective adaptation/compensation negatively impacts the rate of biological aging and, in turn, phenotypic and functional aging. In the scheme, we show only three cycles of epigenetic adaptation, at any point in time; the epigenetic landscape results from the sum of hundreds or even thousands of adaptive cycles that occur throughout life; and some more relevant than others. Importantly, very little is known about how environmental stresses are sensed and encoded into epigenetic changes

Figure 3

The hallmarks of aging are specific biological mechanisms that drive the rate of biological aging. Emerging research reveals that these different mechanisms are strongly interconnected and, therefore, impairment in one mechanism involves the others. In the figure, the octagon and lines within represent evidence for connections between the different mechanisms. The evidence reported is not exhaustive of the literature connecting the hallmarks. According to the geroscience hypothesis, failure in this network of homeostatic mechanisms affects the pace of aging and, in turn, causes a growing susceptibility to diseases. The specific combination of coexisting diseases that occur in each individual depends on their genetic background, as well as exposure to environmental and behavioral risk factors. The resulting multimorbidity is a major cause of disability. Notably, if the number of coexisting diseases is a major proxy biomarker of the pace of aging, it is unsurprising that the number of diseases rather than specific combination is the strongest risk factor for disability