Mois : mai 2024

A long-term female nurse study suggests a link between long-term exposure to certain air pollutants, but not road traffic noise, and the risk of developing dementia [1].

Air pollution as a risk factor

Air pollution is a known risk factor for many conditions, such as cardiovascular diseases, respiratory diseases, Type 2 diabetes, and lung cancer, which we have discussed previously. Similarly, road traffic noise is associated with sleep disturbance and stress, leading to an increased risk of “cardiovascular disease and possibly psychiatric disorders” [2, 3]. Both risk factors share sources, such as road traffic, along with the biological pathways they impact, such as neuroinflammation and brain damage [4], which can lead to dementia.

Studies that examined air pollution (but not road traffic noise) have suggested a link between “long-term exposure to air pollution and the risk of developing dementia.” Specifically, the authors acknowledge the well-researched and established link between dementia and particulate matter with a diameter of ≤2.5 μm (PM2.5) [5]. However, the literature about other air pollutants and traffic noise is inconsistent.

Since previous research on the impact of the combination of air pollution and road traffic noise on dementia risk is limited, in this study, the authors analyzed the data from 25,233 female nurses in Denmark (Danish Nurse Cohort) to establish whether there is a connection “between long-term exposure to both air pollution and road traffic noise and dementia incidence.”

Air pollution and dementia

The data analysis indicated “strong associations between long-term exposure to major air pollutants and incidence of dementia.” The authors elaborate in more detail on which specific pollutants show the association.

The data show that PM2.5 and NO2 have a strong positive association with dementia incidence, while ozone has shown a negative association. Those results are consistent with several previous studies [5]. They also identified an association between black carbon and the incidence of dementia. They report that these associations are linear, meaning that they persist below European Union and World Health Organization standards set for PM2.5 and NO2 air pollution.

Regarding the observed negative association between ozone and the incidence of dementia, the authors hypothesize that it is most likely a result of ozone having lower concentrations near NO2 and black carbon sources. Therefore, the researchers explain, it is not that ozone has a protective effect but that it is more likely to be around where the more dangerous pollutants are not.

While the authors found an association between air pollution and the incidence of dementia, they didn’t identify such a strong association “between road traffic noise and incidence of dementia after adjustment for air pollution.” This observation also agrees with previous research.

Positive effects of exercise

Modifying air pollution exposure is not an easy task and would require major changes in life, such as moving from a big city to a small town or village, which is something not everyone can do. Therefore, the authors looked for something that could mitigate the risk of dementia despite the exposure to air pollution. According to their analysis, physical activity was the one identified factor that modified the association between air pollution and the incidence of dementia.

In this study, they observed that despite being exposed to the same level of PM2.5 pollutants, physically active nurses had a lower risk of developing dementia compared to those with low physical activity levels.

The authors believe that their observation needs to be further assessed and confirmed but that they provide a good starting point for the development of preventive measures against dementia.

Strengths and limitations

As with every study, this one has strong and weak points. One of the main strengths of this study is the cohort the researchers used. This cohort had information on risk factors and behavior, data from nationwide registers, and a 20-year follow-up period. The researchers also used high-quality data regarding air pollution and road traffic noise, to which they had access dating from 14 years before any given nurse was included in the study. Adding the follow-up period, they analyzed around 35 years of exposure.

The cohort they used had many strengths, but it included only females, who have higher risks of developing Alzheimer’s disease. Therefore, there is still a need to investigate whether sex differences play a role in air pollution and dementia association.

The authors believe that there is a need “to identify groups that are most susceptible to harmful air pollution effects on dementia, for which preventive strategies can be designed.”

We show that long-term exposure to air pollution can lead to the development of dementia, even after adjustment for road traffic noise. This brings strong new evidence that supports existing findings in the current literature, suggesting that air pollution is an important risk factor for dementia. Moreover, we present a novel finding that physical activity may help mitigate the adverse effects of air pollution on dementia.

Literature

[1] Tuffier, S., Zhang, J., Bergmann, M., So, R., Napolitano, G. M., Cole-Hunter, T., Maric, M., Antic, S., Brandt, J., Ketzel, M., Loft, S., Lim, Y. H., & Andersen, Z. J. (2024). Long-term exposure to air pollution and road traffic noise and incidence of dementia in the Danish Nurse Cohort. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 10.1002/alz.13814. Advance online publication.

[2] Münzel, T., Molitor, M., Kuntic, M., Hahad, O., Röösli, M., Engelmann, N., Basner, M., Daiber, A., & Sørensen, M. (2024). Transportation Noise Pollution and Cardiovascular Health. Circulation research, 134(9), 1113–1135.

[3] Clark, C., Crumpler, C., & Notley, A. H. (2020). Evidence for Environmental noise Effects on Health for the United Kingdom Policy Context: A systematic review of the effects of environmental noise on mental health, wellbeing, quality of life, cancer, dementia, birth, reproductive outcomes, and cognition. International Journal of Environmental Research and Public Health/International Journal of Environmental Research and Public Health, 17(2), 393.

[4] Jafari, Z., Kolb, B. E., & Mohajerani, M. H. (2018). Chronic traffic noise stress accelerates brain impairment and cognitive decline in mice. Experimental neurology, 308, 1–12.

[5] Wilker, E. H., Osman, M., & Weisskopf, M. G. (2023). Ambient air pollution and clinical dementia: systematic review and meta-analysis. BMJ (Clinical research ed.), 381, e071620.

Ora Biomedical, Inc. announces it has been selected by AFWERX for a SBIR Phase I contract in the amount of $75,000 focused on developing novel therapeutics to address the most pressing challenges in the Department of the Air Force (DAF).

The Air Force Research Laboratory and AFWERX have partnered to streamline the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) process by accelerating the small business experience through faster proposal to award timelines, changing the pool of potential applicants by expanding opportunities to small business and eliminating bureaucratic overhead by continually implementing process improvement changes in contract execution. The DAF began offering the Open Topic SBIR/STTR program in 2018 which expanded the range of innovations the DAF funded and now on May 24th, Ora Biomedical will start its journey to create and provide innovative capabilities that will strengthen the national defense of the United States of America.

“Ora Biomedical was founded on the understanding that age-targeting longevity interventions have a myriad of uses that all go toward promoting the healthiest, longest lives we can live. High-altitude pilots and astronauts are subject to high levels of radiation and other physiological stressors that longevity interventions have shown to be protective against” says Ora Biomedical CTO, Dr. Ben Blue. “We are excited to work with AFWERX and stakeholders in the U.S. Air Force and Space Force to develop longevity interventions for important new uses in maintaining health and maximizing readiness of service-members. This is the first step forward in an innovative project to translate longevity research into real-world applications while meeting the needs of the next era of space exploration”.

Disclaimer: The views expressed are those of the author and do not necessarily reflect the official policy or position of the Department of the Air Force, the Department of Defense, or the U.S. government.

About Ora Biomedical, Inc.

Ora Biomedical, Inc. is a longevity biotechnology company headquartered in Tukwila, WA. Launched out of the University of Washington School of Medicine in 2022, Ora Biomedical develops interventions that maximize readiness and healthy lifespan by targeting the molecular mechanisms that drive aging itself. Ora uses best-in-class robotics and AI to perform high-throughput, high-precision phenotypic testing in live animals with lifespan, healthspan, and stress resistance as primary endpoints. www.orabiomedical.com.

About Air Force Research Laboratory (AFRL)

The Air Force Research Laboratory is the primary scientific research and development center for the Department of the Air Force. AFRL plays an integral role in leading the discovery, development, and integration of affordable warfighting technologies for our air, space and cyberspace force. With a workforce of more than 12,500 across nine technology areas and 40 other operations across the globe, AFRL provides a diverse portfolio of science and technology ranging from fundamental to advanced research and technology development. For more information, visit www.afresearchlab.com.

About AFWERX

As the innovation arm of the DAF and a directorate within the Air Force Research Laboratory, AFWERX brings cutting-edge American ingenuity from small businesses and start-ups to address the most pressing challenges of the DAF. AFWERX employs approximately 325 military, civilian and contractor personnel at six hubs and sites executing an annual $1.4 billion budget. Since 2019, AFWERX has executed 4,697 contracts worth more than $2.6 billion to strengthen the U.S. defense industrial base and drive faster technology transition to operational capability. For more information, visit: www.afwerx.com.

Company Press Contact:

Dr. Mitchell Lee

CEO & Co-Founder, Ora Biomedical, Inc.

mitchell@orabiomedical.com

A new study tested two ketogenic diets and found increases in cellular senescence in multiple tissues [1].

It’s complicated

Ketogenic diets have been a matter of substantial debate. On one hand, they are effective against childhood epilepsy [2], have shown some promise against neurodegeneration [3] and as an adjuvant anti-cancer therapy [4], and might help people lose weight. Anecdotally, people have reported increased energy levels and other positive effects from ketogenic diets, but rigorous studies in humans are still scarce.

On the other hand, ketogenic diets have been linked to increased levels of harmful LDL cholesterol [5], a major factor in cardiovascular disease. A ketogenic diet in epilepsy patients has been associated with increased prevalence of kidney stones and bone fractures [6]. In general, long-term effects of ketogenic diets are not well understood, which gives many experts pause.

In this new study published in Science Advances, researchers from the University of Texas investigated the effects of two ketogenic diets on cellular senescence in mice, reporting intriguing results.

A spike in senescence

The two ketogenic diets (KDs) had vastly different ratios of saturated versus unsaturated fats but produced largely similar results. In both diets, almost none of the calories came from carbohydrates: around 10% came from protein, and around 90% came from fat. Importantly, these are proper ketogenic diets, even if a bit extreme, and they differ from the high-fat diets used by scientists to cause weight gain and metabolic dysfunction in mice, in which only about 40-50% of calories come from fat.

The controls in this study received a balanced diet with most of the calories coming from carbohydrates, and some from protein and fat. Mice in all the groups consumed virtually the same number of calories, and no significant weight gain in any group was reported, although a slight increase in body weight was observed in mice on KDs after 21 days.

At the end of this period, the researchers saw sharp increases in the most popular marker of cellular senescence, senescence-associated beta-galactosidase (SA-β-gal), and in two other markers, histone protein macroH2A.1 (H2AY) and histone 3 lysine 9 trimethylation (H3K9me3), in liver and kidney tissue. Substantial increases in two additional markers, p21 and p16, were detected in four tissues: heart, kidney, liver, and brain.

The prevalence of senescence seemed to be high, with 15% to 20% of the cells in the heart and 10% to 15% of the cells in the kidney stained positive for SA-β-gal. The researchers note that similar levels of senescent cell burden have been reported in murine models of myocardial infarction, lung cell damage, and radiation exposure.

In line with previous research, mice on KDs showed signs of metabolic dysregulation, with some deficit in glucose uptake, but no changes in insulin sensitivity. Levels of triglycerides, LDL cholesterol, and HDL cholesterol were elevated after 21 days.

Senescent cells emit the senescence-associated secretory phenotype (SASP), a mix of various factors that have been reported to contribute to inflammation and induce senescence in nearby cells. The researchers analyzed several pro-inflammatory SASP molecules, TNFα, IL-1β, IL-6, and CCL5, and found significantly elevated levels of them in mice after 21 days of KD:

Similar data from human plasma

The group also analyzed data from two human KD trials at the University of Texas and received similar results. Large increases in two SASP factors (TNFα and IL-1β) in human plasma were detected in both males and females. Interestingly, the increases were slight and statistically insignificant after 90 days of a KD but much more pronounced after 180 days. These results might add to the uneasiness about the long-term effects of KDs. Many interventional studies of KDs in humans are of shorter duration and might have overlooked these effects.

Putting the mice back on regular diets led to a gradual return of the senescence markers to their normal values. According to the researchers, this suggests that KD-related cellular senescence is reversible, at least up to a certain point, and senescent cells get cleared away once the senescence-inducing effects of a KD are no more. The group also found that the negative effects of KDs they had discovered are age-independent, occurring in both young and aged mice.

The results of our in vivo murine experiments in this study, as well as those from other laboratories, reinforce that the effects of KD are complex, with both potential benefits and side effects likely due to multiple factors, including the timing, composition of the diet and the genetics, endocrine factors, and health conditions of the individual. As such, it is proposed that the use of a KD should be considered within the overall scope of personalized medicine, in which the variables for each patient are taken into consideration to determine who will, and who will not, benefit from this dietary intervention or a specific regimen.

Literature

[1] Wei, S. J., Schell, J. R., Chocron, E. S., Varmazyad, M., Xu, G., Chen, W. H., … & Gius, D. (2024). Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Science Advances, 10(20), eado1463.

[2] Neal, E. G., Chaffe, H., Schwartz, R. H., Lawson, M. S., Edwards, N., Fitzsimmons, G., … & Cross, J. H. (2008). The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. The Lancet Neurology, 7(6), 500-506.

[3] Pinto, A., Bonucci, A., Maggi, E., Corsi, M., & Businaro, R. (2018). Anti-oxidant and anti-inflammatory activity of ketogenic diet: new perspectives for neuroprotection in Alzheimer’s disease. Antioxidants, 7(5), 63.

[4] Allen, B. G., Bhatia, S. K., Anderson, C. M., Eichenberger-Gilmore, J. M., Sibenaller, Z. A., Mapuskar, K. A., … & Fath, M. A. (2014). Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox biology, 2, 963-970.

[5] Iatan, I., Huang, K., Vikulova, D., Ranjan, S., & Brunham, L. R. (2024). Association of a low-carbohydrate high-fat diet with plasma lipid levels and cardiovascular risk. JACC: Advances, 100924.

[6] Groesbeck, D. K., Bluml, R. M., & Kossoff, E. H. (2006). Long-term use of the ketogenic diet in the treatment of epilepsy. Developmental medicine and child neurology, 48(12), 978-981.