Month: July 2022

Is boron important to health?

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress, Testosterone , ,

Three papers on boron, starting with a 2022 review:

“Boron-containing compounds (BCC) have effects in the metabolism of living organisms. Information regarding effects and interaction of these compounds was compiled, and potential applications for treating human metabolic disorders was suggested.

Dietary boron supplementation affects metabolism of calcium, magnesium, triglycerides, glucose, amino acids, reactive oxygen, nitrogen species, and hormones such as 17β-estradiol, calcitonin, and 25-hydroxy-cholecalciferol. When food is boron-deprived, there are adverse effects like depressed growth, reduced serum steroid hormone concentrations, changes in plasma and organ calcium and magnesium concentrations, plasma alkaline phosphatase, and bone calcification on animal biological functions.

boron effects

Exploration of basic BCC as metabolism regulators is expanding. Although mechanisms of action are uncertain, limitation of damage induced by reactive species, inflammatory modulation, or activities on some enzymes and membrane transporters are often related to reported effects.

An increasing number of new BCC are emerging as potential tools for prevention, diagnosis, and therapy of metabolism maladies such as diabetes, metabolic syndrome, osteoporosis, cardiovascular, and liver diseases. For those innovative BCC, mechanisms of action are often clear.”

https://link.springer.com/article/10.1007/s12011-022-03346-9 “Boron‑Containing Compounds for Prevention, Diagnosis, and Treatment of Human Metabolic Disorders” (not freely available) Thanks to Dr. Marvin A Soriano-Ursúa for providing a link to a freely available document.

A second paper was a 2021 human study:

“In our elderly population-based sample, a boron-rich diet appeared to be characterized by high intakes of plant foods presumed to be healthy, low intakes of plant foods presumed to be less healthy, and low intakes of all kinds of animal foods.

Higher plasma boron concentrations were related to lower BMI and circulating concentrations of CRP. Plasma boron concentrations were associated with age, phosphate, and plasma lipid metabolism, and showed seasonal variations.

Human intervention studies are warranted to derive causal relationships of circulating and dietary boron with human health and metabolism. Robust databases on boron content of foods are needed to facilitate investigation of dietary boron intake in human studies.

Clarification of the non-/essentiality of trace element boron for human health will form the basis to derive recommendations for a dietary boron intake being sufficient to exert boron’s proposed beneficial physiological roles.”

https://link.springer.com/article/10.1007/s00394-021-02730-w “Plasma boron concentrations in the general population: a cross-sectional analysis of cardio-metabolic and dietary correlates”

As noted in this study, public agencies don’t consider dietary boron content important enough to include in public databases. My daily boron dietary intake estimated from published private databases is:

  • Walnuts, 1.63 mg x (28.3 g / 100 g) = .5 mg
  • Red kidney beans, 1.4 mg x (12 g / 100 g) = .2 mg
  • Chickpeas, 0.71 mg x (40 g / 100 g) = .3 mg
  • Celery, 0.5 mg x (72 g / 100 g) = .4 mg
  • Carrots, 0.3 mg x ( 76 g / 100 g) = .3 mg
  • Coffee .07 mg x 3 cups = .2 mg

2 mg boron daily dietary total

A third paper was a 2022 rodent study:

“Sodium pentaborate pentahydrate (NaB) 1 and 2 mg elemental B/kg supplementation induces the anagen phase in rats via Wnt-1, β-catenin, VEGF, PDGF, and TGF-β1 signaling pathways, which are important molecular mechanisms involved in hair growth.

NaB 4 mg B/kg suppresses these pathways and adversely affects hair growth.”

https://www.sciencedirect.com/science/article/abs/pii/S0946672X22000876 “Sodium pentaborate pentahydrate promotes hair growth through the Wnt/β-catenin pathway and growth factors” (not freely available)

A human equivalent of this study’s rat 1 mg elemental boron intake is (1 mg x .162) x 70 kg = 11 mg.

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Trained immunity epigenetics

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory , , ,

Two papers on trained immunity, starting with a 2022 review:

“Live attenuated vaccines such as the Bacillus Calmette–Guérin, measles-containing vaccines, and the oral polio vaccine have been shown to reduce overall mortality beyond their effects attributable to the targeted diseases.

After an encounter with a primary stimulus, epigenetic and metabolic reprogramming of bone marrow progenitor cells and functional changes of tissue immune cell populations result in augmented immune responses against a secondary challenge. This process has been termed trained immunity.

Main epigenetic events during induction of trained immunity are:

  1. Chromosomal reorganization on the level of topologically associated domains;
  2. Induction of long noncoding RNA activity;
  3. Histone modifications and chromatin accessibility; and
  4. DNA (de)methylation.

trained immunity mechanisms

An epigenetic enzyme belonging to the lysine methyltransferase family, Set7, possesses vital function in β-glucan training of monocytes. When inhibited, trained immunity phenotype is diminished, while Set7 deficient mice cannot establish innate immune memory.

β-glucan is recognized by Dectin-1, and has been known to lead to a shift from oxidative phosphorylation (OXPHOS) to glycolysis as an ATP source. However, a more recent study reported an increase in both glycolysis and oxygen consumption following training, which signals a higher rate of OXPHOS. This discrepancy is explained by the difference in concentration of β-glucan used in the experiments.

Stopping vaccination with measles and polio once the pathogens are eradicated, or replacing live attenuated polio with inactivated polio, should be done with caution, as it may have a substantial impact on childhood mortality. Trained immunity may also represent an important new approach to improve current vaccines, or to develop novel vaccines that combine induction of classical adaptive immune memory and innate immune memory.”

https://www.sciencedirect.com/science/article/pii/S0952791522000371 “Trained immunity: implications for vaccination”

Reference 34 was a 2020 study by two of the same coauthors that provided details on the above discrepancy:

“Findings presented by the current study suggest that the disparity in terms of the role of OXPHOS arises from the stimulatory dose of β-glucan [by intraperitoneal injection]. A β-glucan concentration of 1 μg/mL induces both glycolysis and OXPHOS, whereas a concentration of 10 μg/mL induces glycolysis but inhibits OXPHOS.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30458-7 “The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan”

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The goddess of rainbows

gettingwell4 5+ stars Premium, Acetylcholine, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress, Telomeres , , , , ,

Two 2022 papers, starting with a review of irisin:

“This article is an overview of irisin generation, secretion, and tissue distribution. Its targeting of tissues or organs for prevention and treatment of chronic diseases is systematically summarized, with discussion of underlying molecular mechanisms.

Irisin is an exercise-induced myokine expressed as a bioactive peptide in multiple tissues and organs. Exercise and cold exposure are major inducers for its secretion.

Mechanistic studies confirm that irisin is closely correlated with lipid metabolism, insulin resistance, inflammation, ROS, endocrine, neurotrophic factors, cell regeneration and repairing, and central nervous system regulation. Irisin decreases with age, and is closely associated with a wide range of aging-related diseases.

A number of studies in elderly humans and animal models have shown that exercise can promote the body’s circulation and increase irisin levels in some tissues and organs. Resistance, aerobic, or combined exercise seem to play a positive role. However, exercise could not change serum irisin in some reported studies.

irisin human studies

There are large individual differences in exercise training in the elderly population. Since the half-life of irisin in the body is less than 1 h, it is necessary to pay attention to the time of blood sampling after a single exercise intervention. Some factors that impede detection of irisin levels in vivo include the half-life of irisin protein, sampling time, different tissues, and different health statuses before and after intervention.

It is worth noting that high-intensity exercise shows higher irisin levels even with the same energy expenditure during exercise. Precision studies of irisin in elderly subjects following exercise intervention need to be further clarified.”

https://www.sciencedirect.com/science/article/pii/S1568163722001222 “Irisin, An Exercise-induced Bioactive Peptide Beneficial for Health Promotion During Aging Process” (not freely available) Thanks to Dr. Ning Chen for providing a copy.

A second paper was a human study too recent to be cited by the first paper. I’ll highlight its irisin findings:

“We investigated the complex relationship among DNAm based biomarkers of aging, including DNAmFitAge, a variety of physiological functioning variables, blood serum measures including cholesterol, irisin level, and redox balance, and the microbiome on 303 healthy individuals aged between 33 and 88 years with a diverse level of physical fitness. Regular exercise was associated with younger biological age, better memory, and more protective blood serum levels.

Our research intends to show that regular physical exercise is related to microbiota and methylation differences which are both beneficial to aging and measurable. Our research provides the first investigation between microbiome derived metabolic pathways and DNAm based aging biomarkers.

Irisin levels decrease with age (0.23 average decrease for every 1 year older). We found age-related decreases in irisin levels were attenuated by exercise training. The link between irisin to GrimAge Acceleration and FitAge Acceleration is a novel observation.

HDL is positively associated with irisin. HDL and irisin have complex roles in physiology, and the positive relationship we observe between physical exercise and HDL and irisin align with protective effects seen between HDL and irisin with glucose homeostasis.

This work further supports the biological importance of irisin to the aging process. It is possible our research motivates interventions to boost irisin, like through physical exercise, as possible anti-aging therapies.”

https://www.medrxiv.org/content/10.1101/2022.07.22.22277842v1 “DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation”

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Variable aging measurements

gettingwell4 2-3 stars Required further work, Acetylcholine, Epigenetics, Immune system, Memory, Neurochemicals, Stress, Telomeres , , , ,

Two papers on aging measurements, starting with a 2022 human study:

“We collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration / neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging.

blsa participant ages

We demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity, and shorter survival.”

https://www.nature.com/articles/s43587-022-00243-7 “Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging”

I disagree with this study’s methodology.

1. Although it acknowledged individual variability, nothing was done to positively adjust to those facts. What could have been done per A review of biological variability was:

“Obtain a measurement of variability that is independent of the mean to ensure to not confound changes in variability with shifts in mean.”

2. A usual research practice is to take at least three measurements, and use their average as representative. That wasn’t done here, maybe because of time and expense considerations?

3. An important measurement for physical function was the time to finish a 400 meter walk. I walk more than ten times that almost every day. I use the first 400 meters as a warmup period while getting to the beach to walk eastward and enjoy the predawn light and water animal activity. I concentrate on gait speed during the last third while walking westward on a straightaway bike path.

This study would measure my gait speed as a sometimes old person during the first 400 meters, rather than a gait speed that usually approaches a young person’s during the last 400 meters. Even if I tried to walk my fastest right out of the gate, I wouldn’t be surprised to find a decade or two difference by this study’s measurements between a morning walk’s first and last 400 meter gait speeds.

4. An important cognitive function measurement was the Digital Symbol Substitution Test, apparently taken during subjects’ fasted state? Sometimes after exercising, I’m okay cognitively when starting work in a fasted state at 6:30 a.m., and other times I’m tired.

Two days ago during the last hour of work 1:30-2:30 p.m., I did outstanding work, four hours after eating whole oats for breakfast, and after drinking two coffees and three teas. I took time to put together pieces of puzzles into proper contexts for management’s attention. My bosses weren’t too pleased with the story it told, but it is what it is.

5. Are measurements of how you start what matters? Or is it how you finish, as is common in competitive sports?

This study would measure my cognitive function as a sometimes old person, rather than performance that approaches a young person’s later in the workday. For both physical and cognitive function, my abilities to ramp up and come close to young people’s capabilities are features that I work on, not random, inconvenient measurement variability.

6. Blood measurements were downgraded as having “limited coverage of the four phenotypic domains.” These were taken to fit into specific paradigms and epigenetic clocks. They predictably failed to show causality, as acknowledged with:

“Our analysis showed strong associations between global longitudinal phenotypic score and changes in physical and cognitive function. We did not have sufficient observations to fully separate these two dimensions over time, which would have strengthened the assumption of causality.”

Nowhere in this study was it hinted that all measurements were downstream effects of unmeasured causes. A follow-on study could reanalyze these subjects’ blood samples, MRI, and other measurements for originating upstream factors of signaling pathways and cascades per Signaling pathways and aging and An environmental signaling paradigm of aging.

Reference 35 of this first study was a 2021 human and rodent study that was tossed in as a limitation with:

“We might not have all of the relevant phenotypic measures (for example, more detailed immune profiles) for all participants.”

Its findings included:

“From the blood immunome of 1,001 individuals aged 8–96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians.

Canonical markers of acute infection such as IL-6 and tumor necrosis factor-α were not major contributors to iAge, indicating that, except for IL-1β, infection-driven inflammatory markers of the acute inflammatory response do not contribute to age-related chronic inflammation.

We conducted a follow-up study in an independent cohort of 97 extremely healthy adults (aged 25–90 years) matched for cardiovascular risk factors (including conserved levels of high-sensitivity C-reactive protein), selected from a total of 151 recruited participants using strict selection criteria. In this healthy cohort, inflammation markers were measured using a 48-plex cytokine panel. Only 6 circulating immune proteins were significantly correlated with age, with CXCL9 again the largest contributor to age-related inflammation.

CXCL9 is a T-cell chemoattractant induced by IFN-γ and is mostly produced by neutrophils, macrophages and endothelial cells (ECs). We find that CXCL9 is mainly produced by aged endothelium and predicts subclinical levels of cardiovascular aging in nominally healthy individuals.

We did not find any significant correlation between known disease risk factors reported in the study (BMI, smoking, dyslipidemia) and levels of CXCL9 gene or protein expression. We hypothesize that one root cause of CXCL9 overproduction is cellular aging per se, which can trigger metabolic dysfunction.

As ECs but not cardiomyocytes expressed the CXCL9 receptor, CXCR3, we hypothesize that this chemokine acts both in a paracrine fashion (when it is produced by macrophages to attract T cells to the site of injury) and in an autocrine fashion (when it is produced by the endothelium) creating a positive feedback loop. In this model, increasing doses of CXCL9 and expression of its receptor in these cells leads to cumulative deterioration of endothelial function in aging.

IFN-γ did not increase in expression in our cellular aging RNA-seq experiment, suggesting that there are triggers of CXCL9 (other than IFN-γ) that play a role in cellular senescence in the endothelium that are currently unknown. However, in our 1KIP study, IFN-γ was in fact the second-most important negative contributor to iAge, which could be explained by the cell-priming effect of cytokines, where the effect of a first cytokine alters the response to a different one.

iAge derived from immunological cytokines gives us an insight into the salient cytokines that are related to aging and disease. A notable difference compared to other clocks is that iAge is clearly actionable as shown by our experiments in CXCL9 where we can reverse aging phenotypes. More practical approaches range from altering a person’s exposomes (lifestyle) and/or the use of interventions to target CXCL9 and other biomarkers described here.

Our immune metric for human health can identify within healthy older adults with no clinical or laboratory evidence of cardiovascular disease, those at risk for early cardiovascular aging. We demonstrate that CXCL9 is a master regulator of vascular function and cellular senescence, which indicates that therapies targeting CXCL9 could be used to prevent age-related deterioration of the vascular system and other physiological systems as well.”

https://www.nature.com/articles/s43587-021-00082-y “An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging”

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Beneficial dietary erucic acid?

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebellum, Epigenetics, Lower brain , , , ,

A 2022 review to follow up Caution on broccoli seed erucic acid content?:

“Erucic acid is found to cause cardiac lipidosis in young animals, yet direct evidence of cardiac injury does not exist for young humans. Concerns about erucic acid safety and cardiotoxicity have been published in the press which are based on scientific reports in the 1970s that erucic acid disrupted oxidative phosphorylation and lead to accumulation of lipids in rat cardiac tissue.

Spanish toxic oil syndrome was a major concern, leading to questions about erucic acid cardiotoxicity. Yet it was found that not rapeseed oil per se, rather its carcinogen anilin-dye refined derivative caused cardiotoxicity.

Later, it was understood that reduced ATP production with erucic acid treatment was due to unapt isolation of rat cardiac mitochondria and lipid accumulation that was unique to rats that inherently harbour a low β-oxidative peroxisomal activity and tissue-specific metabolism of erucic acid. Similar structural or metabolic perturbations and tissue injuries were not encountered in monkeys, humans, and pigs.

Potential mechanisms regarding antineoplastic effects of erucic acid in brain tumors:

erucic acid

In children (0 to 14 years), medulloblastomas accounted for less than 10% of brain neoplasias in China, African countries, and Ireland. The ratio was in the range 20%–29% in Brazil, Argentina, Thailand, Korea and Poland, the proportion was 30% in Ecuador, 31% in Taiwan and Jordan.

In adults, the ratio of brain neoplasias diagnosed as glioblastoma was:

  • Below 10% only in China;
  • In the range 10%–29% in India, Thailand, Malaysia, Nigeria, Algeria, Malta, Costa Rica, Ecuador, and the Russian Federation;
  • In the range 30%–49% in some South American countries, Singapore, Taiwan, Japan, Korea, Turkey, Denmark, Iceland, Italy, and Spain among others; and
  • In the range 50%–70% in North America, Puerto Rico, Martinique, Israel, Cyprus, Jordan, Kuwait, and in Oceania.

The low ratio of medulloblastomas in children and of glioblastomas in adult Chinese population cannot be easily attributed to a single genetic and nurture pattern. Very likely, many complex factors interact to explain this difference regarding the Chinese population.

Several hypotheses can be put forward to illuminate the cause of reduced ratios of high grade brain tumors in Chinese which would be of benefit for global reduction and prevention of brain tumors. Erucic acid is very highly consumed in the Chinese diet, and 8-fold higher erucic acid levels exist in Chinese women’s milk in comparison to many other countries.

We hypothesized that dietary erucic acid may be – at least among many factors – associated with reduced ratios of high grade brain tumors in Chinese. If epidemiological and animal studies would prove such an association, an effective, cheap, and relatively non-toxic dietary supplementary strategy may be employed to prevent brain tumors at erucic acid doses lower than those associated with any cardiotoxic effects.”

https://link.springer.com/article/10.1007/s11011-022-01022-4 “Could dietary erucic acid lower risk of brain tumors? An epidemiological look to Chinese population with implications for prevention and treatment” (not freely available) Thanks to Dr. Meric Altinoz for providing a copy.

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Non-CpG methylation

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Stress , , , , , , ,

Three 2022 papers on methylation epigenetic modifiers, starting with a human study focused on mitochondrial DNA non-CpG methylation involving nucleobases other than guanine (arginine, cytosine, or thymine):

“We collected brain tissue in the nucleus accumbens and prefrontal cortex from deceased individuals without (n = 39) and with (n = 14) drug use, and used whole-genome bisulfite sequencing to cover cytosine sites in the mitochondrial genome. Epigenetic clocks in illicit drug users, especially in ketamine users, were accelerated in both brain regions by comparison with nonusers.

Unlike the predominance of CpG over non-CpG methylation in the nuclear genome, the average CpG and non-CpG methylation levels in the mitochondrial genome were almost equal. The utility of non-CpG methylation was further illustrated by the three indices constructed in this study with non-CpG sites having better distinction between brain areas, age groups, and the presence or absence of drug use than indices consisting of CpG sites only. Results of previous studies on the mitochondrial genome that were solely based on CpG sites should be interpreted cautiously.

The epigenetic clock made up of age-related cytosine sites in mtDNA of the control group was consistently replicated in these two brain regions. One possibility for the correlation is the cycle theory that involves mitochondrial activity, mitochondrial DNA methylation, and alpha-ketoglutarate.

As mitochondrial activity fades with aging, mitochondria gradually lose the ability to eliminate methylation on cytosines through alpha-ketoglutarate. Further investigation of the underlying mechanisms is warranted.

To our knowledge, this is the first report that ketamine might change the mitochondrial epigenetic clock in human brain tissues. We believe this is the first report to elucidate comprehensively the importance of mitochondrial DNA methylation in human brain.”

https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-022-01300-z “Mitochondrial DNA methylation profiling of the human prefrontal cortex and nucleus accumbens: correlations with aging and drug use”

A second rodent study focused on RNA methylation:

“We investigated the role of RNA N6-methyladenosine (m6A) in improved resilience against chronic restraint stress. A combination of molecular, behavioral, and in vivo recording data demonstrates exercise-mediated restoration of m6A in the mouse medial prefrontal cortex, whose activity is potentiated to exert anxiolytic effects. To provide molecular explanations, it is worth noting that epigenetic regulation, such as histone modification, microRNA, and DNA methylation all participate in mental and cognitive rehabilitation following exercise.

To generalize these rodent data to humans, we recruited a small group of patients with major depressive disorder with prominent anxiety disorders. Compared to age- and sex-matched healthy individuals, patients displayed decreased circulating methyl donor S-adenosyl methionine (SAM) levels. Serum SAM levels were found to be inversely correlated with the Hamilton Anxiety Scale, suggesting the potential value of SAM as a biomarker for depression or anxiety disorders.

Hepatic biosynthesis of methyl donors is necessary for exercise to improve brain RNA m6A to counteract environmental stress. The dependence on hepatic-brain axis suggests the ineffectiveness of exercise training on people with hepatic dysfunctions.

This novel liver-brain axis provides an explanation for brain network changes upon exercise training, and provides new insights into diagnosis and treatment of anxiety disorders. Exercise-induced anxiolysis might be potentiated by further replenishment of RNA methylation donors, providing a strategy of exercise plus diet supplement in preventing anxiety disorders.”

https://onlinelibrary.wiley.com/doi/10.1002/advs.202105731 “Physical Exercise Prevented Stress-Induced Anxiety via Improving Brain RNA Methylation”

A third paper was a review of mitochondrial-to-nuclear epigenetic regulation. I’ll highlight one mitochondrial metabolite, alpha-ketoglutarate (α-KG):

“Apart from established roles in bioenergetics and biosynthesis, mitochondria are signaling organelles that communicate their fitness to the nucleus, triggering transcriptional programs to adapt homeostasis stress that is essential for organismal health and aging. Emerging studies revealed that mitochondrial-to-nuclear communication via altered levels of mitochondrial metabolites or stress signals causes various epigenetic changes, facilitating efforts to maintain homeostasis and affect aging.

Metabolites generated by the tricarboxylic acid (TCA) cycle, the electron transport chain (ETC), or one-carbon cycle within mitochondria can act as substrates or cofactors to control epigenetic modification, especially histone acetylation and methylation and DNA methylation. α-KG produced in the TCA cycle serves as an essential cofactor for the chromatin-modifying Jumonji C (JmjC) domain-containing lysine demethylases (JMJDs) and ten-eleven translocation (TETs) DNA demethylases. Changes in α-KG levels are capable of driving nuclear gene expression by affecting DNA and histone methylation profiles.

1-s2.0-S0968000422000676-gr2_lrg

α-KG deficiency in progenitor stem cells increases with age. For example, the level of α-KG is reduced in follicle fluids of aged humans, and supplementation with α-KG preserves ovarian function in mice.

α-KG extends lifespan in Drosophila by activating AMPK signaling and inhibiting the mTOR pathway. Supplementing α-KG in the form of a calcium salt promoted a longer and healthier life associated with decreased levels of inflammatory cytokines in old mice.

A human study showed a nearly 8-year reversal in DNA methylation clock biological ages of 42 individuals taking an α-KG based formulation for 4–10 months. α-KG supplementation leads to both demethylation and hypermethylation of some CpG sites in the genome, suggesting that α-KG may have a broader effect on methylation-based aging, such as metabolic functions.

Outstanding questions:

  1. How is production of mitochondrial metabolites regulated both spatially and temporally to elicit epigenetic changes in response to mitochondrial dysfunction?
  2. What are specific epigenetic factors involved in mitochondrial-to-nuclear communications, and how do they cooperate with transcription factors in response to various external and internal stimuli?
  3. Do various mitochondrial metabolites act alone or in concert on the epigenome to regulate the aging process?
  4. Are some organs or tissues more at risk than others in maintaining mitochondrial-to-nuclear communication during aging?
  5. Can intervention of mitochondrial-to-nuclear communications mimic beneficial epigenetic changes to delay aging or alleviate age-onset diseases?”

https://www.sciencedirect.com/science/article/pii/S0968000422000676 “Mitochondrial-to-nuclear communication in aging: an epigenetic perspective”

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Blanching broccoli sprouts

gettingwell4 2-3 stars Required further work, Acetylcholine, Epigenetics, Immune system, Neurochemicals, Stress , ,

Three 2022 papers of interest cited Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease. Let’s start with a fairly straightforward analysis of blanching broccoli sprouts to produce sulforaphane:

“We investigated the effect of blanching conditions to determine the optimal treatment that maximizes sulforaphane (SFN) content in broccoli sprouts. Broccoli seeds grown under controlled conditions were harvested after 11 days from germination and subjected to different blanching conditions based on a central composite design with temperature and time as experimental factors.

Optimum conditions were blanching at 61 °C for 4.8 min, resulting in 54.3 ± 0.20 µmol SFN/g dry weight, representing a 3.3-fold increase with respect to untreated sprouts. This is the highest SFN content reported for sprouts subjected to any treatment so far.

sfn heat response curve

Broccoli sprouts (20 g) were put in plastic bags, which were vacuum-sealed, and then subjected to time (3.4–11 min)–temperature (32–88 °C) combinations.

  • Blanching at 60 °C for less than 8 min resulted in the highest SFN content.
  • Above this temperature, SFN content decreases.
  • The exceptionally high values obtained in this work may be related to treatment, but also to broccoli cultivar and culture conditions.

Different broccoli tissues and developmental stages express different myrosinase isoforms, and catalytic properties of the enzyme may vary among different tissues. Myrosinase found in broccoli florets has an optimal temperature of around 40 °C, and considering myrosinases from other sources, this temperature may vary between 30 and 70 °C.”

https://www.mdpi.com/2304-8158/11/13/1906/htm “Maximization of Sulforaphane Content in Broccoli Sprouts by Blanching”

This first study used heat-only techniques similar to the uncited Enhancing sulforaphane content. It similarly found a 60°C (140°F) myrosinase cliff as have many other uncited studies.

A second paper was a rodent study:

“We investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2–4 month) and aged (20–24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks.

Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, a NRF2 repressor. Sulforaphane treatment did not affect renal NRF2 expression or activity and mitochondrial function in young rats.”

https://www.mdpi.com/2076-3921/11/1/156/htm “Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2”

A human equivalent to this second study’s daily dose was intolerable at (.162 x 15 mg) x 70 kg = 170 mg. I curated this study anyway just to show an example of negligible treatment effects in young animals even when a dose is too high for humans.

A third paper was a review that focused on sulforaphane and its analogs’ chemistry:

“Analysis of the Web of Science database shows that, since 1992, about 3,890 articles have been published on SFN, and over 5,600 on isothiocyanates. Its natural analogs include iberin, alyssin, iberverin, erucin, berteroin, cheirolin, and erysolin.

SFN is a biologically active, natural isothiocyanate found in cruciferous vegetables, and is non-toxic. It has been selected for phase I and II clinical trials, where it is administered in the form of an extract or broccoli sprouts. There are no differences in biological activity between SFN and its natural analogs, such as erucin or alyssin.

No synthetic analogs of SFN described in this review qualified for clinical trials. This is likely due to the toxicity of these compounds in higher doses.”

https://www.mdpi.com/1420-3049/27/5/1750/htm “Sulforaphane and Its Bifunctional Analogs: Synthesis and Biological Activity”

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Supplement evidence and counter-evidence

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress ,

Three 2022 papers, starting with a rabbit study of dietary supplements:

“Adding native type II collagen (NC) to the combination of chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), and hyaluronic acid (HA) showed improvements on osteoarthritis progression. Disease progression was monitored at different time points using magnetic resonance imaging biomarkers, measurement of hyaluronic acid in synovial fluid, and macroscopic and microscopic evaluations of cartilage, synovial membrane and subchondral bone.

CTR (control group–no treatment), CGH (60.38 mg/kg CS + 75.47 mg/kg GlHCl + 3.35 mg/kg HA) and CGH-NC (60.38 mg/kg CS + 75.47 mg/kg GlHCl + 3.35 mg/kg HA + 0.67 mg/kg NC). Clearer colors result in an increase of the frequency of each stage of the disease. Significant differences can be appreciated in the CGH-NC group, compared to the other groups over time.

animals-12-01401-g003

Oral administration of CS with GlHCl and HA, with or without NC, is safe, and provides significant improvements in OA progression. Adding NC leads to better outcomes seen on macroscopic and microscopic evaluation and MRI biomarkers.”

https://www.mdpi.com/2076-2615/12/11/1401/htm “Improved Joint Health Following Oral Administration of Glycosaminoglycans with Native Type II Collagen in a Rabbit Model of Osteoarthritis”

A rodent study of bone growth and similar dietary supplements taken separately found pretty much the opposite:

“Female C57BL/6 mice bred in house were used. Starting at 11 weeks of age, animals were given dietary supplements of either hydrolyzed type I collagen at 1 g/kg, glucosamine sulfate potassium chloride at 300 mg/kg, chondroitin sulfate sodium salt at 250 mg/kg, or fish oil at 1 g/kg. These values were calculated using a body surface area (BSA) calculation from human dosage values of 81.1 mg/kg for collagen, 24.3 mg/kg for glucosamine, 20.3 mg/kg for chondroitin sulfate and 81.1 mg/kg for fish oil.

femur

Our findings indicate that dietary supplements had little impact on bone morphology or mechanics in young female mice and cannot be used to improve bone’s fracture resistance. Bone quality, inferred from material-level mechanical properties and fracture toughness, did not improve with treatment. The only alteration in bone quality was a decrease in elastic modulus with glucosamine or fish oil, which is considered negative and would not be advantageous in preventing fracture.

These data suggest that adding more basic components of the bone matrix into the diet of growing mice does not improve quality of bone tissue. Dietary supplements may be more beneficial in individuals without a balanced diet or in those with an increased risk of fracture, such as those experiencing estrogen loss.”

https://www.nature.com/articles/s41598-022-14068-2 “Dietary supplements do not improve bone morphology or mechanical properties in young female C57BL/6 mice”

This second study cited a 2015 article Translating dosages from animal models to human clinical trials—revisiting body surface area scaling in this context:

“Dosage in this study was determined by using the BSA formula. This technique does have its drawbacks as it does not take into differences in murine metabolism as discussed more in depth elsewhere, but the lack of pharmacokinetic data for dietary supplements in mice prevented a more complex conversion.”

That article has been cited many times, including in a 2022 review:

“Dose-based methodologies for predicting human clinical doses from preclinical data were assessed for oncology drugs. BSA-based approaches were predictive for small molecule oncology drugs, in particular for kinase inhibitors and cytotoxic agents, but prediction was poor for drugs with immune and endocrine components to their mechanisms.

BSA conversion of doses was clearly inappropriate for large molecules. Direct mg/kg-based prediction was more relevant to large molecules with molecular weight > 100 kDa and in particular antibody-drug conjugates.

This approach is theoretically applicable to other therapeutic areas, and if validated in other therapeutic areas, may provide an easy estimate of clinical doses early in the drug discovery and development process to facilitate compound selection and risk management. Later in the drug development process, dose-based methods should be superseded by exposure- and mechanism-based methodologies whenever possible.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087189/ “Predicting Approximate Clinically Effective Doses in Oncology Using Preclinical Efficacy and Body Surface Area Conversion: A Retrospective Analysis”

I’ve used body surface area calculations for human equivalent doses, for example, the small molecule sulforaphane at 177.3 g / mol or 177 Da.

Three of the first study’s human equivalent doses can be calculated by the body surface area factor 0.324 for rabbits since molecular weight of chondroitin sulfate is 463.37 g / mol, glucosamine hydrochloride is 215.63 g / mol, and hyaluronic acid is 403.31 g / mol. Human equivalent doses are:

  • Chondroitin sulfate (.324 x 60.38 mg) x 70 kg = 1,369 mg;
  • Glucosamine hydrochloride (.324 x 75.47 mg) x 70 kg = 1,712 mg; and
  • Hyaluronic acid (.324 x 3.35 mg) x 70 kg = 76 mg.

These three weights are all close to supplement weights advertised to be effective.

Undenatured type II collagen in the first study is 300 kDa, and hydrolyzed type I collagen in the second study varies from 0.3 to 8 kDa. Per the third paper’s recommendation of using mg/kg calculations for large molecules, human equivalent doses would be (0.67 mg x 70 kg) = 47 mg for type II and (81.1 mg x 70 kg) = 5,677 mg for type I, respectively. These two weights are also close to supplement weights advertised to be effective.

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Eat broccoli sprouts for your gut

gettingwell4 5+ stars Premium, Epigenetics, Immune system, Stress ,

Two 2022 papers, starting with a review of sulforaphane’s effects on intestinal inflammation:

“This review summarizes characteristics of intestinal inflammation, the anti-inflammatory mechanism of sulforaphane (SFN) and its various protective effects on intestinal inflammation, and possible future applications of SFN for promoting intestinal health.

SFN is an effective agonist of Nrf2, and it is also able to inhibit expression of inflammation-related genes by activating Nrf2. This kind of anti-inflammatory mechanism has already been confirmed in treatment of intestinal mucositis using SFN.

sulforaphane and gut inflammation

The main absorption site of SFN after oral administration is the small intestine, and its achievable dose for the hind intestine may be lower than the expected dose. Although absorbed SFN can reach the large intestine through intestinal blood and other transportation routes, its therapeutic effect on target tissues may not be as efficient as it would be when the expected dose is directly absorbed by hindgut cells.

Considering that there are several predisposing factors that lead to intestinal inflammation, more research on the effect of SFN on intestinal inflammation with different causes and characteristics should be carried out. Appropriate carriers should be selected according to the onset site and related physiological environment, and a scientific and effective intestinal targeted delivery system for SFN needs to be developed.”

https://pubs.rsc.org/en/content/articlelanding/2022/FO/D1FO03398K “The functional role of sulforaphane in intestinal inflammation: a review” (not freely available). Thanks to Professor Lei Zheng for providing a copy.

Reference 89 – Sulforaphane Normalizes Intestinal Flora and Enhances Gut Barrier in Mice with BBN-Induced Bladder Cancer (not freely available) – in the above graphic was cited for:

“The effect of SFN intervention on intestinal injury in mice with bladder cancer was investigated. It was found that SFN significantly reduced tissue damage in the colon and cecum of mice and normalized the imbalance in intestinal flora caused by BBN, which manifested as an increase in Bacteroides fragilis and Clostridium cluster 1, thus promoting SCFA production.

SFN administration upregulated expression of tight junction proteins including ZO-1, occludin, claudin-1 and glucagon-like peptide 2 (GLP2) to repair damage of mucosal epithelium of the colon and caecum, while reducing release of IL-6 and the secreted immunoglobulin A (SIgA). This study showed for the first time SFN’s alleviating effect on intestinal inflammation may be produced by regulating intestinal flora structure, suggesting that the protective effect of SFN on intestinal health could be multidirectional.”

That study’s 2022 follow-on rodent study also used oral sulforaphane doses:

“This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate underlying mechanisms.

Male C57BL/6 mice were treated with various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment.

  • 5, 10, and 20 mg/kg/day of SFN treatment significantly ameliorated inflammatory damage in mice colon tissue when compared to the colitis group.
  • 5, 10, and 20 mg/kg/day of SFN remarkably mitigated morphological alterations and protected colonic tissue integrity.
  • Nrf2 expression was increased significantly by 5, 10, and 20 mg/kg/day of SFN treatment.
  • SFN partially restored perturbed gut microbiota composition, and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.
  • The contents of butyric acid, iso-butyric acid, valeric acid, and iso-valeric acid were all decreased in DSS-induced colitis mice and in 2.5 mg/kg/day of the SFN treatment group, whereas this decreased tendency was reversed by 10 and 20 mg/kg/day of SFN.

A proposed mechanism by which SFN protects against colitis:

fnut-09-893344-g009

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Signal Transducer and Activator of Transcription 3 (STAT3), and Phase II enzyme UDP-glucuronosyltransferase (UGT) were involved in the protective effect of SFN against DSS-induced colitis.

Nrf2 activation followed by STAT3 signaling pathway play a pivotal role in the protective effect of SFN on colitis. SFN can be considered a potential candidate in the treatment of IBD.”

https://www.frontiersin.org/articles/10.3389/fnut.2022.893344/full “The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism”

A human equivalent dose of the second paper’s oral dose of 20 mg sulforaphane / kg body weight is (.081 x 20 mg) x 70 kg = 113 mg. Per Estimating daily consumption of broccoli sprout compounds, I ate about half that every day by microwaving 3-day-old broccoli sprouts through Week 56, when I cut back to about 35 mg a day. I dialed that back in Week 87 to about 17 mg a day (100 μmol), which is used in a plethora of studies.

I’ve never had ulcerative colitis or inflammatory bowel disease. If I would be diagnosed with either, it would take about five minutes to get back to this study’s equivalent of 10 mg / kg body weight with broccoli seeds and sprouts.

Doubling that to 20 mg may involve taking supplements, though. Haven’t checked for commercial availability lately, but I’ve read a dozen or so studies on encapsulating sulforaphane so that it could reach the colon.

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Green light for BBQ?

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress ,

Two 2022 papers from a clinical trial investigating dietary AGEs’ effects in middle-age people:

“A 4-week diet low or high in AGEs has no effect on insulin sensitivity, secretion, or clearance; vascular function; or overall inflammation in abdominally obese but healthy individuals. These findings require validation in large prospective cohort studies and in populations with established disease such as diabetes and kidney failure.

Our broad array of null findings are not in agreement with those of previous animal and human studies. In mice, baked chow diets high in AGEs led to impaired insulin secretion, insulin resistance and T2DM, and arterial stiffness.

However, usage of baked chow diets may have led to other effects than solely increasing dietary AGEs, such as decreased vitamin bioavailability and increased acrylamide formation. Additionally, AGE levels in baked chow may be higher than those in human food.

jciinsight-7-156950-g267

The present study has several potential limitations. Most importantly, because of the relatively short intervention duration of 4 weeks, we are unable to draw conclusions on longer-term effects of a diet low or high in AGEs.”

https://insight.jci.org/articles/view/156950 “A 4-week high-AGE diet does not impair glucose metabolism and vascular function in obese individuals”

A second paper investigated the trial’s gut microbiota changes:

“A 4-week diet low or high in AGEs has a limited impact on gut microbial composition of abdominally obese humans, paralleling its previously observed limited biological consequences. In contrast, habitual intake of dicarbonyls, reactive precursors of AGEs, was associated with both lower and higher abundances of several genera.

We cannot exclude the possibility that increased intake of dicarbonyls in the high-AGE group influenced our results. Although we observed very limited effects of intervention diets on our outcomes overall, there was an increase in plasma adiponectin after high- compared to low-AGE diet.

Potentially, this was a result of increased intake of dicarbonyls rather than AGEs. Interestingly, most associations between habitual intake of dicarbonyls and genera abundance were not shared between individual dicarbonyls, suggesting unique relationships.

Limitations of our trial:

  • A 4-week diet may be too short to result in changes in the gut microbial composition;
  • Analysis of 16S rRNA instead of metagenomics sequencing;
  • Focus on markers based on relative abundance instead of absolute abundance;
  • It is possible that any beneficial effects of the low-AGE diet on insulin sensitivity were counteracted by less favorable effects on the gut microbiota, ultimately leading to no change in insulin sensitivity after the low- versus the high-AGE diet;
  • We did not measure short and branched chain fatty acids, which could have provided more insight into biological relevance of these associations as well as changes in genera abundance after the low- and high-AGE diets;
  • Regarding estimations of habitual dicarbonyl intake, FFQs may be prone to recall bias, and no FFQ so far has been validated for estimating dicarbonyl intake; and
  • Low- and high-AGE diets were not matched for their glycemic load and index, and these factors may influence endogenous formation of AGEs.”

https://www.mdpi.com/1422-0067/23/10/5328/htm “A 4-Week Diet Low or High in Advanced Glycation Endproducts Has Limited Impact on Gut Microbial Composition in Abdominally Obese Individuals: The deAGEing Trial”

Some previous curations explored topics related to these papers:

  • All about AGEs stated: “AGEs and their precursors cannot be grouped together. Specific, individual information is required for a proper evaluation.”
  • Resistant starch therapy stated: “Microbiome sequencing data are compositional, meaning that gene amplicon read counts do not necessarily reflect bacterial absolute abundances. Instead, read counts are typically normalized to sum to 100%. For this reason, relative abundances of smaller keystone communities (e.g. primary degraders) may increase, but appear to decrease simply because cross-feeders increase in relative abundance to a greater extent. These limitations illustrate the necessity of sufficiently powering RS interventions where microbiome composition is the primary endpoint, collecting critical baseline data and employing appropriate statistical techniques.”
  • Rodent studies mentioned in Caloric restriction’s epigenetic effects and Effects of advanced glycation end products on quality of life and lifespan relied on AGEs in baked chow diets for their findings; and
  • Nano-sulforaphane vs. barbecue chemicals stated: “Women at the early stage of pregnancy should avoid barbecue.”

Happy Independence Day!

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The soluble receptor for AGEs

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress ,

Two 2022 human studies on sRAGE, starting with one of hypoxia-related diseases:

“The receptor for advanced glycation end products is found on endothelial and inflammatory cell surfaces. It binds to circulating advanced glycation end products, activating a proinflammatory protein cascade that contributes to systemic oxidative stress and inflammation.

sRAGE is the soluble isoform of RAGE and acts as a protective decoy by buffering inflammatory ligands, decreasing inflammatory injury. Therefore, low levels of sRAGE are a biomarker of deficient inflammatory control.

We show that plasma concentrations of the anti-inflammatory molecule sRAGE are reduced in patients with chronic obstructive pulmonary disease (COPD) and in patients with obstructive sleep apnoea (OSA). Overlap of COPD and OSA does not lead to an additive effect.

Effective treatment by continuous positive airway pressure (CPAP) of subjects with obstructive apnoeas (with or without associated COPD) increases the level of sRAGE, while in healthy subjects and COPD without OSA, these levels do not change over time. This is the first study to investigate the effect of CPAP on plasma levels of sRAGE.”

https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02092-9 “Soluble RAGE in COPD, with or without coexisting obstructive sleep apnoea”

A second study introduced sRAGE isoforms:

“We explored associations of circulating levels of soluble RAGE, its endogenous secretory (esRAGE) and cleaved (cRAGE) isoforms, AGEs, and their respective ratios with 15-year all-cause mortality in type 2 diabetes. The potential prognostic value of sRAGE as a marker of disease and occurrence of adverse events seems to be suitable for individuals with chronic disease or multimorbidity, and not for the general population.

Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects. At an average follow-up of 15 years, 130 deaths [in T2D subjects] were observed.

A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Kaplan-Meier survival function for patients with type 2 diabetes grouped according to quartiles of the nomogram-based mortality risk score:

diabetes survival

An increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes. The AGEs/cRAGE ratio led to a significant, albeit modest, improvement in the already established RECODe model of predicting 10-year all-cause mortality in type 2 diabetes based on age, sex, ethnicity, smoking, systolic blood pressure, history of major adverse cardiovascular events (MACE), HbA1c, total cholesterol, HDL-C, serum creatinine, and urinary albumin-to-creatinine ratio.

While none of the parameters was significantly associated with development of any complication in patients without complications at the time of enrollment, sRAGE was associated with the development of MACE over a 15-year follow-up in patients with type 2 diabetes who had no history of MACE at recruitment.”

https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01535-3 “Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study”

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AGEs in skin

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress , ,

Here are two 2022 human studies that non-invasively measured advanced glycation end products in skin, starting with one investigating AGEs, carotenoids, and glaucoma:

“This study is the first to simultaneously estimate AGE and skin carotenoid (SC) levels using fingertip sensors in patients with glaucoma.

Elevated intraocular pressure (IOP) is a major risk factor, and lowering IOP through medication or surgery is the main therapeutic option. Numerous risk factors, such as genetics, inflammation, ocular blood flow, and oxidative stress have been proposed by diverse nonclinical and clinical studies; however, the only reliable parameter used in clinical practice is IOP.

Most carotenoids, such as α- and β-carotenes, β-cryptoxanthin, lycopene, lutein, and zeaxanthin, have a maximal absorption wavelength of around 480 nm; therefore, the carotenoid score reflects the bulk of these carotenoid molecules. Intraocular levels of lutein, (3R,3′R)-zeaxanthin, and meso-(3R,3′S)-zeaxanthin, the only carotenoids present in macular pigment, and their antioxidant activity are difficult to estimate directly.

Although carotenoid levels reflect previous intake of vegetables, this lifestyle factor is also difficult to determine. Given that SC levels were mainly associated with vegetable intake for about 1 month, SC can be a good endpoint to assess roles of carotenoids in various diseases in clinical situations.

We found that low SC levels were associated with:

  • Male gender;
  • History of intraocular surgery;
  • Current smoking status;
  • Diabetes;
  • Low vegetable intake score; and
  • High levels of AGEs.

No significant association with glaucoma type was detected. However, AGE levels were higher in exfoliation glaucoma than primary open-angle glaucoma and controls.”

https://www.mdpi.com/2076-3921/11/6/1138/htm “Fingertip-Measured Skin Carotenoids and Advanced Glycation End Product Levels in Glaucoma”

A second study focused on cardiovascular risk:

“AGEs cause arterial stiffness by two main mechanisms:

  • Interaction with arterial walls, which cause functional and structural changes that lead to an over production or cross-linking of collagen, and a decreased level of elastin; or
  • Interacting with receptors for AGEs, thereby activating different signaling pathways, which lead to enhanced production of pro-inflammatory cytokines and vascular adhesion molecules responsible for atherosclerosis.

Our results show that increases in the level of AGEs in Korean patients with type 2 diabetes is associated with arterial pulse wave velocity and vein age, i.e., measures of arterial stiffness. Consequently, subject levels of AGEs were correlated with cardiovascular risk factors. AGE levels can be used as an indicator for CVDs in clinical diagnosis.”

https://www.cell.com/heliyon/fulltext/S2405-8440(22)00859-3 “Skin accumulation of advanced glycation end products and cardiovascular risk in Korean patients with type 2 diabetes mellitus”

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