LongeCityNews Last Updated: 21 November 2024 - 09:47 AM

If you are familiar with research into those parts of lipid metabolism presently considered relevant to the development of atherosclerosis, near entirely focused on the mechanisms by which cholesterol is transported around the body in the bloodstream, then you will know that the CETP protein is considered a target for therapies. This is due to (a) its role in transferring cholesterol between transport particles such as high density lipoprotein (HDL) and low-density lipoprotein (LDL), and (b) suggestive data for gene variants to affect risk of cardiovascular disease.

LDL particles carry cholesterol outwards from the liver into the arteries where atherosclerotic plaques form. HDL particles carry cholesterol back to the liver from the rest of the body. Present therapies aimed at reducing the amount of LDL-cholesterol, such as statins and PCSK9 inhibitors, have their origins in the discovery of human mutants with lower LDL-cholesterol and lower lifetime cardiovascular risk. In practice, the resulting drugs produce only modest benefits, failing to reverse atherosclerosis even when greatly reducing LDL-cholesterol, and only reducing risk of heart attack and stroke by at most 20%, if we are being generous in our interpretation of the data. Similarly, attempts to enhance HDL transport to drain cholesterol from arteries have met with failure.

Today's open access paper is an interesting look at one slice of all of this biochemistry, focused on CETP and whether or not it is a target worth pursuing. The development of many ways to achieve small gains derived from evidence for influence of one gene or another on cholesterol transport has perhaps made some people a little hesitant to jump on yet another similar gene and similar attempt. Yet one can line up a bunch of evidence to suggest that targeting CETP will achieve some benefits, not just for cardiovascular disease, and funding has been found for clinical trials of CETP-targeted therapies.

Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity

Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that is a member of the lipid transfer protein family. It facilitates the bidirectional exchange of cholesteryl esters and triglycerides among lipoprotein particles leading to a net mass transfer of cholesteryl esters from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles. In addition, triglycerides are transferred in the opposite direction from LDL and VLDL to HDL.

Interest in CETP inhibition as a therapeutic target began with the discovery in observational studies that some CETP gene polymorphisms were associated with reduced coronary heart disease (CHD) incidence and CHD mortality, although these results have not been entirely consistent. However, taking all evidence into consideration, observational studies, Mendelian randomization (MR) analyses, and randomized clinical trials of pharmaceutical agents indicate that CETP inhibition confers cardiovascular benefit and reduces risk of atherosclerotic cardiovascular disease (ASCVD). Additionally, emerging evidence suggests that CETP inhibition may promote longevity, presumably by lowering the risk of several conditions associated with aging such as new-onset type 2 diabetes mellitus (T2D), dementia, chronic kidney disease (CKD), and age-related macular degeneration (AMD), as well as promoting survival in septicemia. Some of these effects are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.

At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.

An analysis of data from over twenty thousand people has indicated that greater dietary diversity is associated with slower biological aging [1].

Your health is what you eat

Good dietary habits are linked to many health benefits, and different diets were previously reported to impact the speed of aging and senescence. For example, adherence to the Mediterranean diet is positively associated with increased lifespan and healthspan.

We have also previously reported on some health benefits linked to different dietary patterns, such as associations linking an anti-inflammatory diet and the Mediterranean diet with a reduced risk of dementia, the positive impact of a ketogenic diet on symptoms of multiple sclerosis, the impact of Mediterranean, keto, and plant-based diets on cancer risk and progression, and the metabolic benefits of a ketogenic diet and the Mediterranean diet in pre-diabetes and Type 2 diabetes patients.

The authors of this study did not focus on any specific diet; instead, they focused on the diversity of food consumed by the study participants. They discuss the impact of a diverse diet, which is rich in macronutrients, micronutrients, antioxidants, and bioactive compounds, on the speed of aging.

Biological age is not just a number

Compared to chronological age alone, the relationship between biological age and chronological age is a better estimate of health and the risk of developing age-related diseases. A higher biological age suggests a higher possibility of developing age-related diseases and a higher chance of dying.

The researchers analyzed data from 22,600 participants (49.3% male) with an average age of 48 years from the National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey conducted in the United States. People under 20 years of age, pregnant, and those with no available food intake or biological age data were excluded from the analysis.

The researchers in this study used phenotypic age and Klemera–Doubal method (KDM) biological age to represent the biological age of study participants. Those measures are based on the composite clinical biomarkers.

They used systolic blood pressure, blood creatinine, urea nitrogen, albumin, total cholesterol, glycosylated hemoglobin A1c, percentage of lymphocytes, mean erythrocyte volume, leukocyte count, and alkaline phosphatase as biomarkers for their assessment.

The more diverse, the better

The researchers assessed the dietary diversity score (DDS), which was described as simple, effective, and validated in clinical trials. It measures the number of food groups in one’s diet, based on five major food groups and 18 subgroups. “A higher DDS is generally indicative of a more varied diet and is associated with a broader intake of essential nutrients.” Previous research had reported an association between a higher DDS and a lower risk of chronic diseases such as diabetes mellitus [2] and cardiovascular diseases (CVD) [3].

In the analyzed group, the researchers measured DDS based on the average score from two self-reported 24-hour dietary recalls.

Higher diversity, lower biological age

The researchers used a few models to analyze the data. In the first model, they didn’t include any confounding variables. The second and third models were adjusted for different factors. Model two included demographic factors. The third model also included health metrics, such as cancer, smoking, alcohol consumption, and metabolic data. The researchers performed multiple modeling analyses using different variables (continuous and categorical) and corrected for multiple confounders.

Their results suggested an association between higher DDS and slower biological aging. They note that this relationship is both highly significant (overall p of under 0.001) and linear.

Analysis of the participants’ subgroups divided by different health or demographic factors suggested an inverse relationship between DDS and phenotypic age acceleration across subgroups; however, these results were mainly not statistically significant.

The researchers also performed a sensitivity analysis that ensured the robustness of their observations. They did this analysis using multiple adjustments and concluded that the consistency of all three models suggests “a higher dietary diversity is significantly associated with lower phenotypic age acceleration, regardless of the adjustment methods employed.”

The researchers also explored the idea of oxidative stress being the factor mediating the relationship between dietary diversity and aging. They observed that “the oxidative stress indicator GGT had a significant mediating effect on the association of DDS and phenotypic age acceleration.”

Glutamyltransferase (GGT) was one of the proteins that was significantly lower in people with higher DDS. White blood cell count and neutrophil-lymphocyte ratio, two indicators of inflammation, were also significantly reduced. In contrast, levels of albumin, a potential indicator of anti-inflammatory capacity, and serum klotho, a protein with anti-aging properties, were higher.

Robust results, but without mechanistic understanding

Since this study is based on observational data, it cannot determine the mechanism behind the observed association. Still, the researchers proposed some hypotheses. They believe that oxidative stress and inflammation could be key processes mediating the effect of diet on aging, as a more diverse diet includes more antioxidants and anti-inflammatory compounds that protect cells from aging-related processes. They also consider the possible role of gut microbiota since a diverse diet can help maintain microbial diversity, an important factor for gut health. However, that particular aspect was not explored in this study.

The researchers claim that their results are robust and can be extrapolated to multi-ethnic and otherwise varied populations due to this data’s consistency and analysis.

While this analysis suggested that some associations are mediators, it cannot establish causality, and potential confounding factors (beyond what was tested) cannot be ruled out. The reporting of food intake should also be optimized for future studies.

Overall, this study’s results align with previous research, which linked reduced food diversity to an increased risk of age-related chronic diseases and mortality [2-5]. As the authors note, “promoting dietary diversity may facilitate healthy aging, which has significant implications for public health.”

Literature

[1] Liao, W., & Li, M. Y. (2024). Dietary diversity contributes to delay biological aging. Frontiers in medicine, 11, 1463569.

[2] Zheng, G., Cai, M., Liu, H., Li, R., Qian, Z., Howard, S. W., Keith, A. E., Zhang, S., Wang, X., Zhang, J., Lin, H., & Hua, J. (2023). Dietary Diversity and Inflammatory Diet Associated with All-Cause Mortality and Incidence and Mortality of Type 2 Diabetes: Two Prospective Cohort Studies. Nutrients, 15(9), 2120.

[3] Chalermsri, C., Ziaei, S., Ekström, E. C., Muangpaisan, W., Aekplakorn, W., Satheannopakao, W., & Rahman, S. M. (2022). Dietary diversity associated with risk of cardiovascular diseases among community-dwelling older people: A national health examination survey from Thailand. Frontiers in nutrition, 9, 1002066.

[4] Zheng, G., Xia, H., Lai, Z., Shi, H., Zhang, J., Wang, C., Tian, F., & Lin, H. (2024). Dietary Inflammatory Index and Dietary Diversity Score Associated with Sarcopenia and Its Components: Findings from a Nationwide Cross-Sectional Study. Nutrients, 16(7), 1038.

[5] Chalermsri, C., Rahman, S. M., Ekström, E. C., Ziaei, S., Aekplakorn, W., Satheannopakao, W., & Muangpaisan, W. (2023). Dietary diversity predicts the mortality among older people: Data from the fifth Thai national health examination survey. Archives of gerontology and geriatrics, 110, 104986.

Senescent cells accumulate with age and cause harm via their inflammatory signaling, contributing to the chronic inflammation of aging that is disruptive to tissue structure and function throughout the body. One faction of the research and development community wants to selectively destroy senescent cells via the use of a wide variety of senolytic therapies presently under development. Another faction wants to instead find ways to suppress the inflammatory signaling of these cells. Here find an example of this second area of research, a search for targets that can be manipulated to reduce harmful signaling generated by senescent cells, but which will produce minimal side-effects in non-senescent cells.

In this review, we summarize the current research progress on non-histone high mobility group proteins (HMGs) in the field of aging, particularly their structural characteristics and functional roles in regulating the aging process. As chromatin architectural regulators, HMGs, in collaboration with histones, exert critical influence on chromatin dynamics and gene expression. By competitively binding to specific DNA sites, HMGs alter chromatin accessibility and regulate gene activity, thereby exerting profound effects at various stages of cellular senescence. This regulation involves a wide array of mechanisms and pathways, with a particularly notable impact on the senescence-associated secretory phenotype (SASP) and senescence-associated heterochromatin foci (SAHF).

HMG proteins, particularly members of the HMGA and HMGB families, play pivotal roles in the formation and regulation of SASP and SAHF. SASP comprises pro-inflammatory factors and proteins secreted during cellular senescence, which not only drive the aging process but are also closely associated with various age-related diseases, including chronic inflammation, cardiovascular diseases, and cancer. HMGA proteins promote or inhibit the spread of inflammatory signals by affecting chromatin structure and regulating the expression of SASP-related genes. Meanwhile, HMGB proteins, acting as damage-associated molecular patterns (DAMPs), activate inflammatory pathways and exacerbate the release of SASP. SAHF, as highly compacted heterochromatin regions, silence genes related to proliferation and the cell cycle, marking cells' entry into a state of permanent cell cycle arrest. The dynamic regulation of HMG proteins is crucial for the formation and maintenance of SAHF.

Recent studies have shown that targeting and blocking HMG proteins, particularly HMGB1 and HMGA2, not only reduces the release of SASP but also effectively inhibits inflammatory responses, thereby slowing the progression of age-related diseases. By inhibiting the extracellular release of HMGB1, researchers have found that sterile inflammation and tissue damage can be alleviated, protecting cardiovascular health and delaying the development of age-related cardiovascular diseases. Targeting these proteins has become a key direction in aging research. Compared to traditional therapies, targeting HMG proteins offers a more precise means of modulating age-related pathophysiological processes with fewer effects on normal cells.

Link: https://doi.org/10.3389/fragi.2024.1486281

Generally speaking, one should expect greater disability and disease in later life to correlate with greater mortality. Yet in many mammalian species, including our own, males die younger and females exhibit greater frailty while living longer. Biology is complicated! Here, researchers single out for attention the age-related dysfunction of the immune system that leads to a growing state of unresolved, constant inflammatory signaling. This state of inflammaging is thought to differ in women versus men, and may be one of the more important contributions to the observed sex-specific differences in outcomes.

Aging is a dynamic process that requires a continuous response and adaptation to internal and external stimuli over the life course. This eventually results in people aging differently and women aging differently than men. The "gender paradox" describes how women experience greater longevity than men, although linked with higher rates of disability and poor health status. Recently, the concept of frailty has been incorporated into this paradox giving rise to the "sex-frailty paradox" which describes how women are frailer because they manifest worse health status but, at the same time, appear less susceptible to death than men of the same age. However, very little is known about the biological roots of this sex-related difference in frailty.

Inflamm-aging, the chronic low-grade inflammatory state associated with age, plays a key pathophysiological role in several age-related diseases/conditions, including Alzheimer's disease (AD), for which women have a higher lifetime risk than men. Interestingly, inflamm-aging develops at a different rate in women compared to men, with features that could play a critical role in the development of AD in women. According to this view, a continuum between aging and age-related diseases that probably lacks clear boundaries can be envisioned in which several shared biological mechanisms that progress at different pace may lead to different aging trajectories in women than in men.

Link: https://doi.org/10.1016/j.exger.2024.112619