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Epigenetic Alterations

XPRIZEXPRIZE Los Angeles, CaliforniaPosts: 108 admin
Epigenetic alterations in gene expressions are caused by modification of proteins and changes in the structure of DNA and RNA in a cell. Some of these epigenetic changes are associated with aging, and researchers have extended the lifespan of flies and nematodes by preventing them.

Description

Epigenetics is the study of changes in gene expression that are not caused by changing the DNA sequence itself, but instead by alterations to proteins and the structure of DNA and RNA in the cell. Four lines of evidence support the hypothesis that some epigenetic changes are correlated with the symptoms of biological aging.

Enzymes of the sirtuin (Sir2) protein family take part in silencing certain genes, and researchers have shown that by enhancing their expression they can extend nematodes’ and flies’ life span. Manipulation of certain Sir2 enzymes has mitigated aging symptoms in mice and contributed to healthy aging. Additionally, mice with a genetic deficiency of the SIRT6 enzyme undergo accelerated aging[108]. This evidence has supported the widespread belief that epigenetic alterations - specifically those facilitated via sirtuins - contribute to the aging process.

DNA methylation, an epigenetic change, is correlated with the aging process. In some diseases that resemble accelerated aging (e.g. progeria), the DNA is methylated (i.e. a methyl group gets added to the DNA molecule) in patterns that are similar to those found in normally aged individuals. However, no evidence has been found to prove that an organism’s lifespan can be extended by altering these methylation patterns.

Alterations in the structure of chromosomes is correlated with aging. Certain proteins like heterochromatin protein 1𝛼, which are involved in determining the structure of the chromosomes, dwindle in number during the aging process, but by enhancing their expression, researchers have managed to extend longevity in flies.

A special class of microRNAs, known as gero-miRs, can have an impact on flies’ and nematodes’ lifespan, by regulating transcription of relevant genetic circuits. The gero-miRs’ pattern of expression is itself altered during the aging process.

Impact

The extent to which epigenetic alterations contribute to the aging process and aging-related diseases and conditions is unknown as yet. However, should it be discovered that epigenetic alterations are responsible for a significant part of the aging process, it should be relatively easy to counter them even with today’s technology.

Indeed, early experiments involving the mitigation of certain epigenetic alterations in mice via administration of histone deacetylase inhibitors resulted in neuroprotective effects and prevented age-associated memory loss in mice. Thus, this field is being studied widely in an effort to come up with treatments to the aging process - and possibly even reversing aging.

Difficulties

There has been an effort to uncover and develop therapeutics that work by manipulating certain epigenetic processes. However, the precise way in which epigenetic alterations influence aging is still obscure, and so attempts in this direction have been largely unsuccessful - at least so far.

Comments

  • ymedanymedan Posts: 81 ✭✭
    IMHO, we need to to take a hollistic system view at the genetic interplay among the 4 DNA/RNA pools in our body:

    - Cell nuclei DNA
    - Mitochondria DNA
    - Microbiome DNA
    - Virome RNA

    These are dynamical systems that respond to both external and internal stress signals, which in turn may trigger epigentic alterations in order to either restore a stable equilibrium state or move to a new state.

    When we will hopefully decipher those relations, we would then have the answer. Looking just at the human genome will provide only very partial, sometimes irrelevant, insights for causation vs correlation of such epigenetic changes.
  • marz62marz62 Posts: 25 ✭✭
    edited May 9
    ymedan: There is also Virome DNA (ssDNa, dsDNA).

    Not to shift the topic away entirely from epigenetics/genomics (which is awaiting further research to elucidate the contribution of methylation {and other epigenetic 'writing' such as acetylation} loss or alteration to aging and disease)...

    I like that you include the microbiome here, for, as more and more evidence mounts supporting the role of the microbiota in regulating the immune system (what often goes awry in aged folks, such as with loss of B Cell diversity) as well as the positive responses to immunotherapy (in the case of cancer)...It is becoming clear that the microbiome (its 'robustness' in response to 'assaults') must also play a key supporting role in how well we age.

    But it may go a bit deeper than that. It is entirely likely that this association of the immune response with the microbiome will come down to the epigenomic patterns on microbial DNA (loss of which, such as methylation marks, as we age, may promote over-expression of deleterious gene profiles, turning friendly 'gut bugs' into pathogens,possibly.) This raises the possibility of 'microbiomic aging' (manifesting as an accumulation of mutations, perhaps).

    Some references:

    Gopalakrishnan et al (2018) found a strong association between response to immune checkpoint inhibitors (PD1 - PDL1 axis) and (within-sample) microbiome diversity (specifically, the higher abundance of Ruminococcaceae and Faecalibacterium species in positive responders, verses non-responders).

    [also; Routy et al, 2018, confirmed microbiomic diversity as a factor in 'responders' (i.e., those with a positive immunotherapy response) in patients with epithelial tumors]

    Matson et al (2018) also identified eight species that were enriched (in fecal samples) in patients who responded positively to immunotherapy (for metastatic melanoma), including Bifidobacterium longum, "which is associated with responsiveness to cancer immunotherapy in mice."

    General reference: https://www.nature.com/articles/nrmicro.2018.12

  • ymedanymedan Posts: 81 ✭✭
    Road to cell death mapped in the Alzheimer's brain

    Newly identified mechanisms offer novel avenues for targeted therapeutic development

    VAN ANDEL RESEARCH INSTITUTE
  • marz62marz62 Posts: 25 ✭✭
    @ymedan - thanks for that press release!

    So, it seems that gene enhancer-based reactivation of cell division (via hyper-loss of key epigenetic marks) instead of letting old cells die (as in normal age progression), triggers a series of toxic cellular outcomes (including the plaques associated with AD).

    Here's the salient quote (3 paragraphs) from the press release:

    "They [Labrie et al] found that in normal aging, there is a progressive loss of important epigenetic marks on enhancers. This loss is accelerated in the brains of people with Alzheimer's, essentially making their brain cells act older than they are and leaving them vulnerable to the disease.

    At the same time, these enhancers over-activate a suite of genes involved in Alzheimer's pathology in brain cells, spurring the formation of plaques and tangles, and reactivating the cell cycle in fully formed cells -- a highly toxic combination.

    "In adults, brain cells typically are done dividing. When enhancers reactivate cell division, it's incredibly damaging," Labrie said. "The enhancer changes we found also encourage the development of plaques, which act as gasoline for the spread of toxic tangles, propagating them through the brain like wildfire. Taken together, enhancer abnormalities that promote plaques, tangles and cell cycle reactivation appear to be paving the way for brain cell death in Alzheimer's disease."
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