Fight Aging!

Most forms of air pollution (with a particular focus on fine particles) are now well established to contribute to age-related conditions at the level of exposure that is experienced in much of the industrialized world. Typically matters are worse in less wealthy regions, particularly those using solid fuel for domestic cooking and heating. Nonetheless, there is enough of a contribution even in wealthier regions for studies to show meaningful differences to health depending on varying levels of exposure. A study in the Puget Sound region, for example, found that greater exposure increased dementia risk.

The specific mechanisms by which air pollution accelerates the onset and progression of common age-related conditions are largely linked to chronic inflammation. Unresolved inflammatory signaling is disruptive to tissue structure and function, and the interaction of pollutants with cells in the lungs and airways promotes inflammatory signaling that affects the whole body.

Today's open access paper reviews what is known of these mechanisms in the context of a specific condition, Parkinson's disease. This neurodegenerative condition has a strong connection to the aging of the gut microbiome and intestines, as that is where the misfolded α-synuclein that drives the condition can originate. It then spreads through the nervous system to the brain, where it produces the first evident symptoms of Parkinson's disease, and eventually dementia and death. The greater the burden of inflammation placed upon body and brain, the faster this will happen.

Air Pollution and Parkinson's Disease Pathology: Clinical Evidence and the Molecular Mechanisms Linking Airborne Toxicants to Neuroinflammation and Neurodegeneration

Studies have reported positive correlations between exposure to particulate matter (PM), nitrogen oxide (NOx), ozone (O3), and an increased risk of Parkinson's disease (PD). Beyond the incidence of PD, studies have examined the linkage between long-term air pollution contact and the risk of hospitalization, mortality, and disease progression among PD patients, suggesting that air pollution may not only lead to the development of PD but also aggravate the clinical course and outcomes of the disorder.

Several pathways have been proposed to involve the biological processes underpinning the connection between air pollution and PD. Extensive research in animal models and human studies has reported that PD is interrelated with significant modifications in gut microbial structure, including the reduction of anti-inflammatory short-chain fatty acid (SCFA)-producing bacteria and the enrichment of opportunistic pathogens. Exposure to air pollution has been shown to disrupt the gut microbiome, potentially resulting in increased gut permeability, the propagation of pathogenic processes, and inflammation that may contribute to the development and progression of PD.

It has been demonstrated that interaction with air pollutants can also motivate α-synuclein to misfold and accumulate, as well as the impairment of other key proteins involved in neuronal function and homeostasis. Air pollution has been linked to oxidative stress and neuroinflammation, which can lead to the induction of multiple transcription factors, NRF2, NF-κB, and MAPK, forcing dopaminergic neurons to malfunction and degenerate. Furthermore, the incorporation of ultrafine PM in the brain, particularly in the olfactory bulb and other vulnerable zones, has been associated with excitotoxicity, mitochondrial dysfunction, and the propagation of neuroinflammatory processes that may be responsible for the pathophysiology of PD.

Despite progress in investigating the association between air pollution and PD, findings remain inconsistent. Some studies have recognized positive links between exposure to pollutants such as PM, NOx, and O3 and an increased risk of PD, whereas other studies have not found statistically important associations. These discrepancies underscore the complexity of the interactions between environmental exposures, genetic predisposition, and any other modifiable risk factors in the pathogenesis of PD. Mechanistic studies have offered useful insights into the biological pathways linking air pollution to PD. However, the precise mediators and dose-response relationships remain unclear. Furthermore, regional differences in pollution levels, exposure assessment methods, and population characteristics may contribute to the variability in findings across epidemiological studies. There is a growing need for well-designed, large-scale longitudinal studies with standardized exposure assessment methods to more accurately quantify the long-term effects of specific air pollutants on PD risk and progression.

The state of the cardiovascular system has a strong impact on the aging of the brain. The brain requires an sizable supply of energy, delivered via the bloodflow, and suffers when that supply is reduced. With age, the vascular system loses smaller vessels, while larger vessels become damaged. Loss of physical fitness also reduces blood supply. Additionally, damaged blood vessels allow leakage of unwanted cells and molecules into the brain to produce inflammation, while blood vessel walls can be a source of inflammatory signaling themselves. Increased blood pressure can be avoided or controlled, but where hypertension is present, it is harmful to vessels in the brain, causing a toll of small ruptures that damage brain tissue over time. All of this adds up. The study here is one of many to link vascular health with cognitive decline leading to dementia.

Midlife vascular risk factors are associated with both dementia and premature death; however, their combined association with dementia-free survival years remains unclear. We conducted a prospective cohort study (Atherosclerosis Risk in Communities study) with participants from 4 US communities. Participants were alive and dementia-free at age 55 years and had visit 2 (1990-1992) measurements of diabetes (self-report, medication use, or HbA1c ≥ 6.5%), hypertension (blood pressure ≥ 140/90 mm Hg or medication use), and current smoking. Vascular risk burden was defined as the count of these risk factors (0-3).

Among 12,409 participants (mean age 56.2 ± 5.2 years), over a median follow-up of 26.3 years, 3,008 developed dementia and 5,238 died dementia-free. Compared with 0 risk factors, 3 risk factors were associated with higher hazards of dementia (hazard ratio [HR] 2.69) and death without dementia (HR 5.61). Higher vascular burden was associated with fewer dementia-free survival years, declining from 30.1 years for 0 risk factors to 17.5 years for 3 risk factors. In conclusion, maintaining optimal midlife vascular health was associated with up to 12.6 additional dementia-free survival years, reflecting both higher dementia hazard and markedly higher competing mortality.

Link: https://doi.org/10.1212/WN9.0000000000000152

From one perspective, the XPRIZE Healthspan research prize is a way to encourage what should be happening to a far greater extent in the development of means to treat aging as a medical condition, which is to assess which approaches are better than others. The field spends too much time on approaches that cannot improve on lifestyle choices, for example. Ideally this competitive assessment requires some useful consensus definition of aging and age-related degeneration to work against - which is presently lacking; aging clocks are a step in that direction, but cannot be trusted to provide useful results for any given novel intervention targeting mechanisms of aging. Thus the XPRIZE Healthspan leadership chose to go with benchmarking competing approaches against narrow definitions of function in a few areas where fairly standardized methodologies exist: muscle, cognition, immune capacity.

Launched in 2023, the seven-year, $101 million XPRIZE Healthspan competition is the first incentive health competition of its kind dedicated to accelerating the development and clinical testing of proactive, accessible interventions that target the biology of aging itself. Rather than treating age-related diseases after they occur, the competition challenges teams to restore muscle, cognitive, and immune function by at least 10 years - with an ambitious target of 20 years - in adults ages 50 to 90, all within one year or less of treatment. If successful, these breakthroughs have the potential to help millions of people live longer, healthier, and more independent lives.

Today, XPRIZE announced the 20 Finalist teams advancing to the next stage of the competition, marking a major milestone in the global race to transform how we age. Among the finalists, 10 teams from the United States, South Korea, Japan, and China were selected as Milestone 2 awardees and will each receive a $1 million award, totaling $10 million in milestone funding, to accelerate the development and clinical testing of innovative therapies designed to extend healthy years of life. In addition to funding, the teams will gain access to key clinical testing resources to support the next phase of their work.

Together, the finalist teams represent a diverse range of approaches targeting the biology of aging, including: novel medicines and biologics designed to improve metabolism, reduce inflammation, protect neurons, and repair damaged cells; regenerative approaches, including stem cell and gene-based therapies, that support cellular repair, energy production, and tissue health; extracellular vesicles and other next-generation delivery technologies that harness the body's natural processes to promote rejuvenation; AI-enabled precision health and personalized care models that combine data, existing medicines, nutraceuticals, and lifestyle interventions to optimize healthy aging.

Link: https://www.xprize.org/news/20-healthspan-finalist-teams-advance-in-the-race-to-extend-healthy-aging