Tag: Chromatin

Magnesium’s pivotal role in slowing aging’s impact
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Aging is associated with many biological, physiological, and psychological changes, some of which include a decline in cognitive function, greying of hair, frailty, and increased risk of contracting certain diseases. Aging also increases the risk of chronic diseases such as diabetes, hypertension, and cardiovascular events.

Most older adults experience chronic magnesium deficiency or hypomagnesemia, which may be due to low dietary magnesium content, reduced intestinal absorption, and increased urination. In a recent review published in the journal Nutrients, researchers discuss the role of magnesium in aging.

Study: Magnesium and the Hallmarks of Aging. Image Credit: monticello / Shutterstock.com

The role of magnesium in telomere attrition

Telomeres are present at both ends of chromosomes, thereby protecting them from degradation and fusion with other chromosomes to preserve genetic information. Between 50-100 base pairs of telomeric DNA are lost after each cell division; therefore, telomeres shorten as age advances.

When a telomere attains a critical short length, cells recognize it, and replication is attenuated, which results in cell senescence. Previous studies have indicated that magnesium maintains telomeric chromatin structure and integrity, as well as supports telomerase regulation.

Genomic instability

Genomic instability, which involves DNA damage, chromosomal abnormalities, and mutations, is a key driver of aging. Genomic instability occurs due to oxidative stress, epigenetic alterations, inadequate DNA repair, and telomere maintenance.

Throughout the cell cycle, magnesium is essential for stabilizing chromatin assembly. Furthermore, DNA grooves have specific binding sites for magnesium, thereby demonstrating its role in DNA conformation.

Insufficient magnesium levels cause DNA instability through oxidation stress, as various enzymes involved in DNA repair are activated by magnesium. Thus, magnesium plays a crucial role in the DNA replication process and preservation of genome stability.

Epigenetic alterations

Epigenetic alterations refer to the modification of genomic expression without alterations in DNA sequence. The epigenome can be altered through lifestyle factors, diets, and pharmaceutics. Additionally, the age-related inflammatory environment and inhibitory molecules released from stressed cells may lead to epigenetic alterations, which can modify cellular function.

Several studies have highlighted the association of magnesium with epigenetics. For example, hypomagnesemia causes down-regulation of hepatic 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters, which affect the metabolism of neonatal offspring.

Loss of proteostasis

Proteostasis alterations are associated with weak protein stability and misfolded proteins. Several age-related chronic diseases, such as Alzheimer’s and Parkinson’s disease, have been attributed to the dysregulation of proteostasis. Importantly, low magnesium levels in the brain may lead to many neurological disorders, including epilepsy, Alzheimer’s disease, Parkinson’s disease, and migraines.

Magnesium downregulates tumor-necrosis factor α (TNF-α) and interleukin 1β (IL-1β) production, in addition to supporting the clearance of amyloid β (Aβ) precursor molecules by proteasomal degradation pathways. Magnesium also inhibits the N-methyl-D-aspartate (NMDA) receptor and increases excitatory neurotransmission.

Mitochondrial dysfunction

The mitochondria is involved in multiple cell signaling processes that determine cell fate, including cellular survival and death by apoptosis. Dysfunctional mitochondria can lead to the persistent reduction in cellular adenosine triphosphate (ATP) levels for prolonged periods, which may lead to chronic inflammation, cellular damage, and oxidative stress. These conditions are also linked with age-associated diseases, such as Alzheimer’s disease and Parkinson’s disease.

Magnesium binds with ATP to form the Mg-ATP complex. The presence of intracellular free magnesium has been associated with the development of hypertension and diabetes, both of which are conditions that are more prevalent in older adults. Low magnesium levels are also associated with oxidative stress damage through reduced lipid peroxidation and antioxidant enzyme activity.

Cellular senescence

Cellular senescence is associated with cellular stress and irreversible DNA damage. Additional features of aging include senescence-associated mitochondrial dysfunction, altered nutrient and stress signaling, and autophagy/mitophagy dysfunction.

Certain cellular alterations that occur during senescence are similar to those caused by hypomagnesemia, including reduced protection against oxidative stress damage, cellular viability, cell cycle progression, and enhanced risk of transcription factor expression.

Stem cell exhaustion

Human tissues are maintained by stem cells due to their self-renewing capacity. More specifically, stem cells can differentiate into progenitor cells, from which various tissues are developed.

Previous studies have shown that a reduction in the hemopoietic cells’ regenerative potential due to aging is associated with the reduced production of adaptive immune cells, which is otherwise known as immunosenescence.

Magnesium is strongly linked with immune responses. For example, magnesium is a cofactor for the production of immunoglobulins (Ig), antibody-dependent cytolysis, macrophage response to lymphokines, and immune cell adherence.

Conclusions

Since the aging trajectory is variable, it can be modulated through magnesium intake and lifestyle changes. The current review discusses the importance of suitable magnesium levels throughout life, which may contribute to healthy aging.
Journal reference:

Dominguez, L. J., Veronese, N., & Barbagallo, M. (2024). Magnesium and the Hallmarks of Aging. Nutrients 16(4); 496. doi:10.3390/nu16040496
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February 14, 2024
Immune system in the blood of Alzheimer’s patients found to be epigenetically altered

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A new Northwestern Medicine study has found the immune system in the blood of Alzheimer’s patients is epigenetically altered. That means the patients’ behavior or environment has caused changes that affect the way their genes work.

Many of these altered immune genes are the same ones that increase an individual’s risk for Alzheimer’s. Northwestern scientists theorize the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors.

It is possible that these findings implicate the peripheral immune response in Alzheimer’s disease risk. We haven’t yet untangled whether these changes are reflective of brain pathology or whether they precipitate the disease.”

David Gate, lead investigator, assistant professor of neurology at Northwestern University Feinberg School of Medicine

The study was published Feb. 9 in Neuron.

Previous research showed that many of the mutated genes putting a person at higher risk for Alzheimer’s are in the immune system. But scientists primarily studied the central immune system in the brain because Alzheimer’s is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system.

Gate decided to study the blood. He and colleagues discovered every immune cell type in Alzheimer’s patients has epigenetic changes, indicated by open chromatin. Chromatin is the packaging of the DNA within cells. When chromatin is open -; or exposed -; the cells’ genome is vulnerable to alterations.

Then, Gate examined which genes are more open in these immune cells. He discovered that a receptor -; CXCR3 -; on the T cells was more exposed. Gate believes CXCR3 functions like an antenna on T cells that allows the cells to enter the brain. T cells do not normally enter the brain because they can cause inflammation.

“The brain is emitting a signal that it is damaged, and the T cells are homing to that signal by their antenna, CXCR3,” Gate said.

“T cells can be very toxic in the brain, but we also don’t know if these cells might be attempting to repair the damage in the brain,” Gate said.

Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes.

“Altogether, these findings indicate that immune function in Alzheimer’s patients is significantly altered,” Gate said. “It could be that environmental factors, like pollutants, or infections that a person has in their lifetime cause these epigenetic changes.”

The findings revealed several genes that may be therapeutic targets for manipulating the peripheral immune system. Next steps in the research are preclinical studies using in vitro culture systems and animal models to test these targets.

Other Northwestern authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova and Lynn van Olst.

The title of the article is “Epigenetic dysregulation in Alzheimer’s disease peripheral immunity.”

The research is supported by National Institute of Neurological Disorders and Stroke grant NS112458 and National Institute on Aging grant AG078713, both of the National Institutes of Health, Bright Focus Foundation, Alzheimer’s Association and Cure Alzheimer’s Fund.

Source:

Journal reference:

Ramakrishnan, A., et al. (2024) Epigenetic dysregulation in Alzheimer’s disease peripheral immunity. Neuron. doi.org/10.1016/j.neuron.2024.01.013.

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February 10, 2024
Is there an association between vitamin D, immunocompetence, and aging?

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In a recent review published in the journal Nutrients, researchers explored the role of an individual’s immunocompetence in the responsiveness to vitamin D.

They discussed the modulation of immunocompetence via the epigenetic programming function of the vitamin D receptor (VDR) and its ligand and highlighted the impact of aging on immunocompetence.

Study: Vitamin D and Aging: Central Role of Immunocompetence. Image Credit: Iryna Imago/Shutterstock.com

Background

Vitamin D plays a crucial role in bone health by regulating calcium homeostasis and preventing conditions like rickets and osteomalacia. However, its influence on immunity extends beyond this function.

Vitamin D deficiency, linked to modern lifestyle factors like limited sun exposure, affects the endogenous production of active vitamin D metabolites.

The inactive vitamin D₃ is converted to active 1,25(OH)2D3 in the liver and kidneys, which acts as a hormone and affects various tissues. Notably, various cells, including those of the innate immune system, can produce 1,25(OH)2D3 locally, contributing to auto- and paracrine effects. This compound acts as a ligand of high affinity for VDR, regulating the expression of numerous genes.

The vitamin D status, indicated by serum 25(OH)D3 levels, categorizes individuals into deficient, insufficient, or sufficient groups. Vitamin D responsiveness varies among people due to genetic and epigenetic factors influencing molecular responses.

Low responders, constituting about 25% of the population, may have increased susceptibility to diseases related to compromised immunity. The VDR-based modulation of immunocompetence may contribute to aging and reduce the risk of age-related diseases.

The present review offers insights into the immunomodulatory functions of vitamin D and its impact on various health aspects beyond bone metabolism.

Vitamin D signaling

VDR binds specifically to genomic DNA, recognizing the motif RGKTSA. In complex with retinoid X receptor (RXR), VDR preferentially binds to direct repeat sequences in the euchromatin. Various “pioneer factors” facilitate VDR in opening chromatin, which is crucial for efficient binding.

Chromatin accessibility and VDR binding can be assessed using next-generation sequencing technologies, including ChIP-seq (chromatin immunoprecipitation sequencing) and ATAC-seq (assay for transposase-accessible chromatin using sequencing), especially in peripheral blood mononuclear cells.

Genomic regions of vitamin D target genes demonstrate changes in chromatin accessibility and VDR binding after vitamin D₃ supplementation.

Enhancers and transcription start site regions, even at a considerable linear distance, can interact via DNA looping within the same topologically associating domain, influencing gene expression.

VDR’s genomic actions involve protein-protein interactions with the Mediator complex and RNA polymerase II, influencing transcription. Vitamin D also exerts epigenomic effects, altering DNA methylation, histone modifications, and chromatin organization, dynamically shaping the cell’s epigenetic landscape.

These genomic and epigenomic effects contribute to vitamin D’s modulatory role in hematopoiesis and immunocompetence, affecting human immune cells both in vitro and in vivo.

Epigenetic programming of immune cells

Throughout embryogenesis and adult cellular differentiation, stem and progenitor cells undergo epigenetic programming, determining the function of terminally differentiated cells. 1,25(OH)2D3 plays a crucial role in this process, influencing hematopoiesis and the differentiation of immune cells.

Hematopoietic stem cells (HSCs) differentiate into various blood and immune cell types, and 1,25(OH)2D3 regulates embryonic HSC numbers.

Various transcription factors influenced by vitamin D drive the differentiation of myeloid progenitor cells into granulocytes and monocytes. Vitamin D is also the differentiation of monocytes into dendritic cells and macrophages.

Epigenetic programming by vitamin D contributes to innate immune cell adaptation, modulating responses to infections, inflammation, and diseases.

Variability in vitamin D status and response index among individuals affects the epigenetic programming of monocytes and derived cells, emphasizing the potential of optimized vitamin D₃ supplementation for supporting proper immune cell epigenetics and overall immunocompetence. However, further research is needed to validate this concept fully.

Decline in immunocompetence during aging

Aging involves accumulating molecular damage, resulting in cellular dysfunction and weakened organs. Immunocompetence, crucial for appropriate immune responses, declines with age, leading to increased susceptibility to infections and diseases.

The thymus atrophies, diminishing the production of T-cells, and “inflammaging” ensues. However, interindividual differences exist, and some individuals may display relatively higher immunocompetence.

Lower immunocompetence correlates with accelerated aging and heightened disease risks. Vitamin D sufficiency may protect against cancers by preserving immunocompetence.

Adequate vitamin D levels could stabilize immune resilience, safeguard against diseases, and contribute to healthy aging by mitigating various hallmarks of aging, including inflammation and cellular stress.

Conclusion

In conclusion, the active form of vitamin D plays a crucial role in modulating the epigenome of immune cells, particularly in monocytes.

The observed associations between vitamin D deficiency, increased disease risk, and accelerated aging may be attributed to diminished immunocompetence.

Considering individual responsiveness, a precautionary daily vitamin D3 dose of 1 µg (40 IU)/kg body mass is suggested, exceeding general recommendations but staying within safe limits to strengthen immunocompetence. The researchers emphasize personalized vitamin D supplementation to safeguard against prevalent diseases and promote healthy aging.

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February 1, 2024