LongeCityNews Last Updated: 30 October 2025 - 01:03 PM

Synucleinopathies such as Parkinson's disease are caused by the spread of misfolded α-synuclein through the brain. α-synuclein is one of a small number of proteins that, when misfolded, can encourage other molecules of the same protein to misfold in the same way, aggregating to form toxic solid deposits and a halo of disrupted biochemistry. Misfolded α-synuclein is particularly pernicious as it can pass from cell to cell, spreading pathology as it goes. Here, researchers explore one of the ways in which misfolded α-synuclein harms cells, by interfering in the supply of the energy store molecule adenosine triphosphate (ATP) that is produced by mitochondria and is essential to cell function.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and the most frequent movement disorder today, for which there is only symptomatic treatment. Amyloid fibers of the protein α-synuclein (αSyn) constitute the major content of pathological intraneuronal inclusions, Lewy bodies, found in dopaminergic neurons in PD patient brains. Amyloid toxicity has been attributed to the ability to seed new amyloids, to translocate between cells, to deteriorate membranes, to be a sink for functionally relevant proteins by binding, and to sterically block cellular functions. Amyloids were considered chemically inert until we showed that αSyn amyloids catalyzed hydrolysis of ester and phosphoester bonds in vitro.

Lewy pathology, i.e., amyloids, is also found in the nuclei of cells, and our earlier work showed αSyn monomers to interact with DNA. When we extended this to amyloids, we found that αSyn amyloid interactions with DNA promote strand breaks in the DNA. Thus, the chemical reactivity of αSyn amyloids may contribute to the noted widespread DNA damage observed in PD patients.

Neurons have disproportionately high energy demands compared to other organs but lack energy fuel storage (such as fatty acids and glucogen). In contrast to many other cells, neurons must continuously produce ATP from glucose to meet the cellular demands and maintain energy homeostasis. Decline in brain ATP levels has been connected to both Alzheimer's and PD. There is evidence that αSyn amyloids perturb mitochondria, resulting in lower ATP production.

Here, we combine biochemical, biophysical, computational, and structural methods to probe the interaction between αSyn amyloids and ATP. We report that αSyn amyloids display catalytic activity toward ATP hydrolysis in vitro. We propose that ATP depletion by αSyn amyloid hydrolysis may disturb the local energy balance in neuronal cells.

Link: https://doi.org/10.1002/advs.202508441

The Dog Aging Project has in recent years enrolled thousands of companion animals into multiple cohorts and studies, including a study of the effects of rapamyin as a treatment to slow aging in dogs. Much of the value of the Dog Aging Project taken as a whole lies in the generation of a large database of omics data that can then be mined for insights into aging in this species, some fraction of which will be applicable more generally to aging in other mammals - such as our own species.

In today's open access paper, researchers present their findings from an analysis of metabolomic data derived from the Dog Aging Project's smaller Precision Cohort, 784 dogs for whom more extensive biological data was gathered. Aging modifies circulating levels of a sizable fraction of the 133 metabolites measured in blood plasma from this cohort, which could be used as the basis for an aging clock, or inspected more closely for single measures that serve as biomarkers of aging.

The data points to increased levels of various acetylated amino acids as biomarkers of aging, the acetylated forms of phenylalanine, tryptophan, alanine, and glutamine that are produced when acetylated proteins are broken down. Changes in levels of these modified amino acids correlate with declining kidney function. It will be interesting to see whether human data exhibits a similar pattern; there is a fair amount of literature on the connection between protein acetylation and aging, similarly for protein acetylation and cellular senescence, and for other related topics.

Protein Catabolites as Blood-Based Biomarkers of Aging Physiology: Findings From the Dog Aging Project

Our understanding of aging has grown through the study of systems biology, including single-cell analysis, proteomics, and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) aims to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs.

Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP, 784 animals. By incorporating extensive metadata and whole genome sequencing, we overcome the limitations inherent in breed-based estimates of genetic effects, and probe the physiological basis of the age-related metabolome. We identified effects of age on approximately 36% of the 133 measured metabolites. We also discovered a novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which are generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. The only known source of free ptmAAs is the breakdown of protein, and we found additional evidence for protein catabolism within the metabolome. We found that clinical measures of kidney function at least partially mediate the age associations of the ptmAAs. These results suggest that ptmAAs accumulate with age among dogs and may serve as a biomarker of aging physiology.

This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

A recent study discovered an association between visceral and, to a lesser extent, hepatic fat with cardiovascular risk factors and carotid atherosclerosis. This association persists even after adjusting for cardiovascular risk factors [1].

Beyond BMI

Body mass index (BMI) is a metric that compares height to total weight, including fat located under the skin (subcetaneous fat). It is easy to calculate, which is part of why it is a standard measurement of health. Some scientific studies use BMI in the assessment of health and disease risk, and they associate high BMI with many health risks, including cardiometabolic risk and various diseases [2].

However, there might be better metrics than BMI for assessing health-related risk. The researchers find that accumulation of fat around the visceral organs (visceral adipose tissue) and fat within the liver (hepatic fat) are both related to cardiometabolic risk and arteriosclerosis and can be a better reflection of those risks than BMI. Visceral fat is also linked to multiple conditions, such as type 2 diabetes mellitus (T2DM), hypertension, elevated cholesterol, increased inflammation, reduced cognitive function, and cancers [3, 4].

Large cohorts with precise data

In a recent study, the researchers set out to investigate whether visceral adipose tissue and hepatic fat are associated with carotid atherosclerosis, a condition defined as a buildup of plaques in the carotid arteries that supply blood to the brain.

They used the data from two cohorts: The Canadian Alliance for Healthy Hearts and Minds (CAHHM), which included 6,760 Canadians with a mean age of 57.1, and the UK Biobank (UKB), which included 26,547 participants with a mean age of 54.7. While the number of analyzed participants makes it a large sample size, which adds to the strength of the analysis, the cohort was mainly of European heritage, which limits the generalizability of the results to other races and ethnicities.

The datasets included information regarding health, demographics, and lifestyle. To measure carotid atherosclerosis, they used an MRI scan of the abdomen and carotid arteries (CAHHM) and an ultrasound of carotid intima-media thickness (CIMT), which is the thickness of the inner two layers of the carotid arterial wall (UKB). The authors note that the MRI assessment yields the most accurate data; it is more sensitive than an ultrasound of carotid intima-media thickness and is much better than some indirect measures, such as waist circumference or elevated liver function tests.

Positive associations

The Canadian cohort reported that visceral adipose tissue and hepatic fat fraction were associated with higher cardiovascular risk factor burden and higher odds of hypertension, diabetes mellitus, and dyslipidemia. They also noted that an increase in visceral adipose tissue volume, but not hepatic fat fraction, was associated with a higher carotid wall volume, which persisted after adjustment for cardiovascular risk factors.

The United Kingdom cohort showed a positive association between visceral adipose tissue volume and carotid-intima media thickness, as well as between hepatic fat fraction and carotid-intima media thickness, even after adjustment for cardiovascular risk factors.

The researchers also pooled the data from both studies. This analysis showed a positive association of visceral adipose tissue and hepatic fat fraction with metrics of carotid atherosclerosis, even after adjustment for cardiovascular risk factors. However, authors advise caution when interpreting those results, as the two polled studies used different measurements of carotid atherosclerosis.

Adding to the evidence

“This study shows that even after accounting for traditional cardiovascular risk factors like cholesterol and blood pressure, visceral and liver fat still contribute to artery damage,” said Russell de Souza, co-lead author of the study and a faculty member in the Mary Heersink School of Global Health and Social Medicine, and member of the Centre for Metabolism, Obesity and Diabetes Research (MODR) and at McMaster. “The findings are a wake-up call for clinicians and the public alike.”

This study adds to the growing body of evidence about visceral fat’s impact on health and cardiovascular disease risks. Previous studies on hepatic fat are less clear about its relationship to the development of cardiovascular diseases; some show the association between hepatic fat and the risk of such diseases, while others don’t [5-8].

Visceral fat is emerging as an important biomarker for cardiovascular conditions. As the authors wrote, “the International Atherosclerosis Society and International Chair on Cardiometabolic Risk Working Group on Visceral Obesity hold the position that among adiposity measures, visceral fat is the strongest predictor of adverse CV risk and is a better predictor of subclinical atherosclerosis than waist circumference” [3].

Visceral or liver “fat is metabolically active and dangerous; it’s linked to inflammation and artery damage even in people who aren’t visibly overweight. That’s why it’s so important to rethink how we assess obesity and cardiovascular risk,” said Sonia Anand, the corresponding author of the study, a vascular medicine specialist at Hamilton Health Sciences and a professor in the Department of Medicine at McMaster. “You can’t always tell by looking at someone whether they have visceral or liver fat.”

As of now, the primary way to reduce visceral and hepatic fat is through changing behavior, and in this study, the authors recommend exercising, maintaining a healthy body weight, and changing to a Mediterranean diet while avoiding food generally considered ‘unhealthy’, such as foods that are fried, heavily processed, or have dded sugar. They also suggest that time-restricted eating, very low-calorie ketogenic diets, and low-fat vegan diets may have a positive effect.

Literature

[1] de Souza, R. J., Pigeyre, M. E., Schulze, K. M., Lamri, A., Al-Khazraji, B. K., Awadalla, P., Beyene, J., Desai, D., Despres, J. P., Dummer, T. J. B., Friedrich, M. G., Hicks, J., Ho, V., LaRose, É., Lear, S. A., Lee, D. S., Leipsic, J. A., Lettre, G., Moody, A. R., Noseworthy, M. D., … Anand, S. S. (2025). Visceral adipose tissue and hepatic fat as determinants of carotid atherosclerosis. Communications medicine, 5(1), 424.

[2] Brixner, D., Ghate, S. R., McAdam-Marx, C., Ben-Joseph, R., & Said, Q. (2008). Association between cardiometabolic risk factors and body mass index based on diagnosis and treatment codes in an electronic medical record database. Journal of managed care pharmacy : JMCP, 14(8), 756–767.

[3] Neeland, I. J., Ross, R., Després, J. P., Matsuzawa, Y., Yamashita, S., Shai, I., Seidell, J., Magni, P., Santos, R. D., Arsenault, B., Cuevas, A., Hu, F. B., Griffin, B., Zambon, A., Barter, P., Fruchart, J. C., Eckel, R. H., International Atherosclerosis Society, & International Chair on Cardiometabolic Risk Working Group on Visceral Obesity (2019). Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. The lancet. Diabetes & endocrinology, 7(9), 715–725.

[4] Anand, S. S., Friedrich, M. G., Lee, D. S., Awadalla, P., Després, J. P., Desai, D., de Souza, R. J., Dummer, T., Parraga, G., Larose, E., Lear, S. A., Teo, K. K., Poirier, P., Schulze, K. M., Szczesniak, D., Tardif, J. C., Vena, J., Zatonska, K., Yusuf, S., Smith, E. E., … Canadian Alliance of Healthy Hearts and Minds (CAHHM) and the Prospective Urban and Rural Epidemiological (PURE) Study Investigators (2022). Evaluation of Adiposity and Cognitive Function in Adults. JAMA network open, 5(2), e2146324.

[5] Al Rifai, M., Silverman, M. G., Nasir, K., Budoff, M. J., Blankstein, R., Szklo, M., Katz, R., Blumenthal, R. S., & Blaha, M. J. (2015). The association of nonalcoholic fatty liver disease, obesity, and metabolic syndrome, with systemic inflammation and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis, 239(2), 629–633.

[6] Mellinger, J. L., Pencina, K. M., Massaro, J. M., Hoffmann, U., Seshadri, S., Fox, C. S., O’Donnell, C. J., & Speliotes, E. K. (2015). Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study. Journal of hepatology, 63(2), 470–476.

[7] Pisto, P., Santaniemi, M., Bloigu, R., Ukkola, O., & Kesäniemi, Y. A. (2014). Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study. BMJ open, 4(3), e004973.

[8] Kotronen, A., & Yki-Järvinen, H. (2008). Fatty liver: a novel component of the metabolic syndrome. Arteriosclerosis, thrombosis, and vascular biology, 28(1), 27–38.

The practice of calorie restriction is well established to slow aging, albeit to a lesser degree in long-lived species than in short-lived species. Calorie restriction memetics are compounds that trigger some of the same beneficial mechanisms involved in the response to reduced calorie intake. They do not capture the full effect, but the best of them (such as rapamycin) are nonetheless still beneficial enough to command attention from the research community.

Like rapamycin, the calorie restriction mimetic spermadine has been shown to upregulate the operation of autophagy, an effect presently thought to be the most important aspect of the response to calorie restriction. Long-term treatment with spermadine modestly extends life in mice, to a lesser degree than rapamyin (~10% versus ~25%). Here, researchers focus on clinical trials that measured spermadine levels or treated with spermadine and observed the outcome on cognitive function; the data is mixed, but also not all that consistent, a common issue in the field.

Increasing evidence suggests that caloric restriction (CR) and intermittent fasting may elevate endogenous levels of spermidine (SPD), a polyamine compound now being investigated as a natural caloric restriction mimetic (CRM) candidate. Beyond its endogenous role in cellular metabolism, SPD can be obtained from dietary intake and synthesised by commensal gut microbiota. SPD is involved in several critical biological processes, including cell growth, differentiation, and autophagy, a fundamental mechanism for cellular maintenance and repair. Recognised as a natural inducer of autophagy, SPD is considered an antiageing compound with properties resembling those of CR, positioning it as a potential CRM.

This article provides a comprehensive synthesis of current evidence on the impact of SPD on cognitive ageing, drawing from both observational and interventional studies. A systematic search of major electronic databases identified 22 relevant studies, comprising 4 interventional trials and 18 observational studies. Observational evidence suggests a potential association between SPD levels and cognitive function, with indications of a protective effect against cognitive decline. However, the variability in results, driven by inconsistencies in SPD measurement methods (eg, brain tissue, blood serum/plasma, red blood cells, or dietary intake), poses challenges to drawing definitive conclusions.

Interventional studies offer preliminary evidence suggesting that SPD supplementation may serve as a potential strategy to mitigate age-related cognitive decline. Some studies have indicated positive cognitive effects of SPD supplementation on cognitive function, such as improvements in memory performance and cognitive assessments. However, inconsistencies remain. The observed differences may be potentially due to variations in SPD dosage, the sensitivity of cognitive assessment tools, and other methodological differences.

Link: https://doi.org/10.1136/gpsych-2024-101723