LongeCityNews Last Updated: 13 June 2025 - 11:59 PM

Cholesterol attached to LDL particles leaves the liver to be transported in the bloodstream to tissues throughout the body. Along the way, this is expected to contribute to development of atherosclerosis in blood vessel walls via deposition of excessive cholesterol in some locations. Patients with homozygous familial hypercholesterolemia, who exhibit loss of function mutations in the LDL receptor and enormously elevated LDL cholesterol in blood, demonstrate that past a certain point there is a dramatic acceleration of atherosclerosis resulting from too much transported cholesterol. Untreated, these patients typically die in their 30s from heart attack or stroke.

What about the rest of the population with a more normal varied range of LDL cholesterol levels, however? The consensus on lowering LDL cholesterol as the dominant approach to reduce atherosclerotic cardiovascular disease risk is not without its challengers. Physicians note that most of the aged patients who present with a first heart attack or stroke do not have elevated LDL cholesterol. Epidemiologists note that the data suggests that the mechanisms of atherosclerosis vary considerably across the population. People respond very differently to cholesterol levels and pharmacological strategies to reduce them. This is one of the reasons why very large trials are needed to see effect sizes resulting from lowered LDL cholesterol.

Today's open access paper is an example of the body of literature that challenges the consensus on the practice of setting targets for LDL cholesterol levels, and the relevance of LDL cholesterol to disease. A reasonable view of the situation is that some fraction of the population does suffer when LDL cholesterol is too high, and thus does benefit from the therapeutic strategy of lowering LDL cholesterol - but at present there is no good way to identify in advance whether any given individual is in that group. The underlying biochemistry is not fully understood, and outcomes arise only slowly over time, a situation in which producing greater understanding is necessarily expensive, and thus few groups are willing to make the effort.

Is Targeting LDL-C Levels Below 70 mg/dL Beneficial for Cardiovascular and Overall Health? A Critical Examination of the Evidence

Over the past two decades, the strategy for managing cardiovascular disease (CVD) risk with lipid-lowering therapy has changed significantly. LDL-cholesterol (LDL-C) targets in guidelines have been progressively lowered from 100 mg/dL (2.6 mmol/L) or less to 70 mg/dL (1.8 mmol/L) or less for high-risk patients and 55 mg/dL (1.4 mmol/L) or less for very high-risk patients. The reduction in target LDL-C levels was stated as justified based on the appearance that intensive lipid-lowering therapy offered additional cardiovascular benefits compared to the standard regimens.

The establishment of low LDL-C targets in CVD prevention was based on the premise that there is a linear relationship between LDL-C levels and CVD risk. However, this premise faces several challenges: (1) The supposed direct correlation between LDL-C levels and atherosclerosis progression is questionable; (2) The systematic reviews that provided the foundation for this assumption have several limitations, including extrapolation of results for LDL-C levels beyond observed data; (3) Potential bias due to the ecological fallacy stemming from meta-regression results based on study-level rather than patient-level analyses; (4) Inconsistent findings from trials specifically designed to investigate the relationship between LDL-C targets and CVD risk; (5) Research documenting greater longevity of elderly individuals with familial - as well as non-familial - hypercholesterolemia contradicts the premise that lower LDL-C levels are ideal.

In this paper, we address these challenges point by point, providing evidence to support each argument. We also point out that LDL-C is a hybrid measure composed of heterogeneous particles, with varying atherogenicity depending on the size of the particles. Finally, we address evidence that pleiotropic effects of lipid-lowering therapies, particularly statins, may contribute to cardiovascular benefits, independent of LDL-C reduction. This paper, therefore, presents evidence to challenge current LDL-C targets of 70 mg/dL or less in patients at high CVD risk.

A new study has lent more support to previous epidemiological data that ties the popular sugar substitute erythritol to elevated cardiovascular risk [1].

Deceptively sweet

Sugar substitutes have been around for decades, and while some people have reported deceases in weight and blood glucose, a growing body of research suggests there might be some downsides to guiltless sweetness.

Recent epidemiological studies have found a link between the popular sweetener erythritol and increased cardiovascular and cerebrovascular risk. A study from 2023 showed that elevated erythritol levels were positively associated with non-fatal and fatal heart disease and stroke, both in males and females, across several population subgroups in the United States and Europe [2].

Populational studies can neither establish a causal relationship nor provide a mechanistic explanation. However, in this case, the researchers also conducted a small prospective trial showing that exposure to an equivalent of 30 grams of erythritol, the usual dose found in one standard-size artificially sweetened drink, significantly increases clot-forming (thrombogenic) potential both in vitro and in vivo. A new study from the University of Colorado Boulder, published in the Journal of Applied Physiology, went even further, revealing a possible mechanism behind this association.

Multiple signs of cardiovascular dysfunction

The researchers worked on an in vitro model based on brain microvascular endothelial cells. These cells line capillaries in the brain and are important for maintaining healthy blood flow, blood-brain barrier integrity, and low inflammation levels. “Endothelial cell dysfunction is a major antecedent to heart disease and stroke,” the authors wrote, “however, the effects of erythritol on endothelial cell function are not well understood.”

After subjecting the cells to the same dose of erythritol as in the earlier 2023 study for 24 hours, the researchers found that the levels of reactive oxygen species (ROS), harmful molecules that can oxidize and damage DNA, proteins, and lipids, accelerating aging and disease processes, was 75% higher than in control cells.

Expression of catalase and SOD-1 was 25% and 45% higher, respectively. Catalase is an antioxidant enzyme that breaks hydrogen peroxide down into water and oxygen, and SOD-1 converts superoxide radicals into less-reactive hydrogen peroxide. Together, they form a frontline enzymatic shield against oxidative stress, which the cells apparently used with limited success, to mitigate the increased levels of ROS.

According to the paper, these results suggest that, at minimum, erythritol does not negatively affect cells’ antioxidant machinery. “However,” the authors note, “we cannot rule out the possibility that longer exposure or repeated chronic exposure to erythritol would result in diminished SOD-1 and catalase bioavailability and in further exacerbation of ROS production.”

The researchers then assessed the production of nitric oxide (NO), a compound that relaxes blood vessel walls, curbs platelet sticking, and dampens inflammation to preserve healthy vascular tone and endothelial function. They found changes in phosphorylation, a type of post-translational modification, of eNOS, an enzyme central to NO production, which ultimately resulted in a 20% decrease in NO production. Diminished NO bioavailability is a hallmark of endothelial dysfunction and is linked to elevated cardiovascular risk [3].

Another worrying sign was that erythritol treatment caused a 30% increase in endothelin-1, a peptide that constricts blood vessels, elevates blood pressure, and fosters vascular inflammation. Along with lower NO availability, this can eventually lead to disrupted blood flow and increased risk of stroke.

Lastly, the researchers assessed the levels of t-PA, the enzyme that transforms plasminogen, an inactive blood protein, into plasmin, the active form that chews through fibrin and melts clots. Baseline t-PA levels were identical in the treated and control cells. However, erythritol blunted the increase in t-PA in response to thrombin, which is how an endothelial cell reacts to clotting risk.

Approach with caution

The researchers admit that in vivo studies are needed to confirm their findings. However, this is already an important addition to the current epidemiological data that points to potential cardiovascular risks from artificial sweeteners.

“While erythritol is widely used in sugar-free products marketed as healthier alternatives, more research is needed to fully understand its impact on vascular health,” said Auburn Berry, a graduate student at the University of Colorado Boulder and first author of the study. “In general, people should be conscious of the amount of erythritol they are consuming on a daily basis.”

Literature

[1] Berry, A. R., Ruzzene, S. T., Ostrander, E. I., Wegerson, K. N., Fersiva, N. O., Stone, M. F., … & DeSouza, C. A. (2025). The Non-Nutritive Sweetner Erythritol Adversely Affects Brain Microvascular Endothelial Cell Function. Journal of Applied Physiology.

[2] Witkowski, M., Nemet, I., Alamri, H., Wilcox, J., Gupta, N., Nimer, N., … & Hazen, S. L. (2023). The artificial sweetener erythritol and cardiovascular event risk. Nature medicine, 29(3), 710-718.

[3] Yetik-Anacak, G., & Catravas, J. D. (2006). Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascular pharmacology, 45(5), 268-276.

Mitochondria are power plants, hundreds of them in every cell. A mitochondrion is descended from symbiotic bacteria, essentially a wrapper around the electron transport chain, which is a complex system that produces either heat or molecules of adenosine triphosphate (ATP), a chemical energy store used to power the cell. It also produces reactive oxidative molecules as a side-effect of its energetic process of operation, which the cell treats as both a source of damage to be repaired and a signal to adjust operations. Improving mitochondrial function slows aging. Interesting, so does mild sabotage of the electron transport chain, causing the cell to react to the reduced supply of ATP and increased generation of oxidative molecules by increasing its maintenance and defense efforts - the benefits outweigh the harms. This is all very complex, however; any change cascades to produce second order effects, and it is hard to predict in advance whether a novel mitochondrially targeted intervention will be beneficial or harmful in aggregate. Once the results are demonstrated it is then hard to understand why it is beneficial or harmful.

Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical - and, in the case of metformin, clinical - longevity benefits.

More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress.

Link: https://doi.org/10.3390/biom15050614

The gut microbiome is made of thousands of microbial species in various proportions, some helpful, some harmful. The development of means to accurately measure the composition of the gut microbiome, by sequencing the 16S rRNA gene that exhibits characteristic species-level differences, has enabled the scientific community to connect changes in the gut microbiome to aging, health, and disease. This mapping of the gut microbiome as a contributing factor in aging and age-related diseases is still in the relatively early stages, but as the field progresses we should expect to see increased interest in the development of novel, improved means to alter the gut microbiome as form of therapy.

The composition of the gut microbiome is fairly resilient to short-term changes induced by diet, present probiotic and prebiotic supplements, mild antibiotic use, and the like. It will bounce back. Over decades of life, however, changes do occur in the balance of microbial populations, and they are not favorable. Inflammatory microbes grow in number at the expense of microbes that generate metabolites necessary for optimal tissue function. Some of this is a consequence of long-term shifts in diet in older individuals, some of it is the decline of the immune system in its role as gardener of the gut microbiome, some of it is other factors. The relative importance of each of these items has yet to be concretely determined.

Fortunately there are ways to permanently change the gut microbiome. Flagellin immunization will direct the immune system to more aggressively remove problem microbes, reshaping the whole microbiome into a more favorable configuration of populations. Fecal microbiota transplantation from a young donor to an old recipient will rejuvenate the balance of populations, and has been shown to produce health and longevity benefits in animal studies. The problem there is that it is unclear as to what exactly constitutes a beneficial microbe, and so it seems likely that fecal microbiota transplantation will be discarded in favor of culturing specific known mixes of microbes that can be delivered once via enteric capsules or similar to achieve a similar but more controlled outcome.

The gut microbiota and aging: interactions, implications, and interventions

Aging is associated with notable shifts in the composition and function of the gut microbiota. Research indicates a decrease in microbial diversity and changes in the abundance of specific bacterial groups in older individuals compared to younger counterparts. For instance, there tends to be an increase in Escherichia coli and other Proteobacteria and a decrease in beneficial bacteria like Bacteroides and Bifidobacterium, essential for gut health and overall wellbeing. Centenarians, a unique subset of elderly individuals, serve as a fascinating model for studying longevity and investigating gut microbiota alterations that could potentially facilitate healthier aging. Centenarians exhibit a noteworthy trend: an elevation in genera such as Akkermansia, which holds potential implications for longevity.

These alterations in the gut microbiota are influenced by several factors, including dietary changes, reduced physical activity, increased medication use, and physiological changes in the gastrointestinal tract such as decreased gut motility. The decline in beneficial bacteria and the proliferation of potentially pathogenic microbes contribute to an imbalanced gut environment, often referred to as dysbiosis. Dysbiosis in the elderly has been associated with various age-related conditions, like inflammaging, cognitive decline, neurodegeneration, insulin resistance, type 2 diabetes mellitus, cardiovascular disease, and cancer.

Given the critical role of the gut microbiota in aging and age-related diseases, there is a growing interest in microbiota-targeting interventions to promote healthy aging. In addition to dietary modifications, probiotics, non-viable probiotics (paraprobiotics), prebiotics, synbiotics, and microbial soluble factors (postbiotics) have garnered significant attention for their potential to modulate the gut microbiota and enhance the health of the elderly. Although still in the experimental stages for age-related conditions, fecal microbiota transplantation (FMT) has shown promise in restoring a healthy microbiota and improving metabolic and immune functions in older adults, based on animal studies.