Fight Aging!

Whenever reading about the effects of an intervention and environmental influence on aging clocks, one has to spend a little time thinking about what it is that these clocks measure and what is known of how the clocks behave. An aging clock is produced from a reference data base of biological measures taken at various ages. If an individual has a pattern of data that matches up to people with an older chronological age in the reference database, then that individual is said to exhibit accelerated biological aging. Is it accelerated biological aging? That is where one has to be careful with definitions.

For most clocks, particularly epigenetic clocks, there is next to no understanding of how the measures making up the clock, such as whether a CpG site on the genome is methylated or not, relate to forms of molecular damage and dysfunction related to aging. The clock measures something, but then researchers have to prove that the something is relevant. We might think that a clock is broadly good and useful if it accurately reflects the known epidemiological data regarding risks of age-related mortality and disease that result from interventions and environmental influences. But we'll never know in certainty that a clock is broadly good and useful; even a few good results fail to tell us how a clock will perform for some other, different intervention.

Nonetheless, researchers are testing all sorts of interventions and environmental factors for their effects on aging clocks in the hope that a large enough pool of data will provide confidence in the use of clocks to assess novel interventions aimed at slowing or reversing aging. Today's open access paper is an interesting example of the type, in which clocks are assessed for their ability to reflect the known effects of heat exposure on mortality and late life health.

Ambient outdoor heat and accelerated epigenetic aging among older adults in the US

Extreme heat contributes to a range of health conditions. Health impacts from heat are particularly adverse among older adults due to age-related declines in thermoregulatory functions. Although links between extreme heat and morbidity and mortality are well established, knowledge of the biological underpinnings is limited. The physiological toll exacted by heat events may not manifest immediately as clinical conditions. Rather, these environmental insults may elicit subclinical deterioration at the biological level, accelerating biological aging, which precedes the subsequent development of diseases and disabilities. Animal studies suggest that epigenetic alteration is a strong candidate for a potential biological mechanism. Severe heat stress can induce a "maladaptive epigenetic memory," which can be coded through changes in DNA methylation (DNAm) patterns. DNAm, arguably the most well-studied epigenetic marker, is known to be responsive to environmental stressors, modulating gene expression and exerting downstream effects on morbidity and mortality risks.

This study examines the association between ambient outdoor heat and epigenetic aging in a nationally representative sample of US adults aged 56+ (N = 3,686). The number of heat days in neighborhoods is calculated using the heat index, covering time windows from the day of blood collection to 6 years prior. Multilevel regression models are used to predict acceleration in principle component (PC) versions of PhenoAge (PCPhenoAge) and GrimAge (PCGrimAge), and in DunedinPACE. More heat days over short- and mid-term windows are associated with increased PCPhenoAge acceleration (e.g., B for prior 7 days: 1.07 years). Longer-term heat is associated with all clocks (e.g., B for prior 1 year: 2.48 years for PCPhenoAge, B for prior 1 year: 1.09 year for PCGrimAge, and B for prior 6 years: 0.05 years for DunedinPACE). Subgroup analyses show no strong evidence for increased vulnerability by sociodemographic factors.

The temporal patterns may reflect different magnitudes and types of biological responses to heat stress occurring in varying time frames. The observed short- and mid-term associations of heat on PCPhenoAge acceleration may be indicative of immediate physiological responses to heat stress. Previous research has identified specific methylation pathways that may potentially underlie these observations.