Meeting abstract
https://doi.org/10.21857/ypn4oc4189
Changes in gene regulation in brain aging
Goran Šimić
*
Ena Španić Popovački
Lea Langer Horvat
* Corresponding author.
Abstract
The greater the mortality caused by environmental factors, the less natural selection will favor the
maintenance of somatic cells, giving preference to the vitality of germ cells. Since the pressures of natural
selection act more strongly towards positive effects in earlier life stages (gene variants that lead to
dysfunction before puberty will quickly be outcompeted by alleles that favor the production of healthy
offspring), the aging process is a consequence of the absence of these pressures after the reproductive
period. Cognitive abilities peak during the reproductive phase and need only remain stable until
offspring become independent. Events after reproduction are less significant, so the heritability impact
on longevity is generally low: approximately 0.23 for men and 0.26 for women (Herskind et al.,
1996). Genetic effects on lifespan shorter than 60 years are minimal, and their impact then increases
proportionally with age. After reaching sexual maturity, the priorities shift from adaptation and cognitive
development to finding a mate, procreating, and caring for offspring, leading to a reduction in
synaptic density and plasticity in the cerebral cortex (Huttenlocher and Dabholkar, 1997). The duration
of reproduction and neurodegeneration in mammals is proportional regardless of differences in
lifespan, suggesting that the aging process is similar across mammalian species, differing only in pace.
This is likely due to a unique epigenetic clock that “ticks” at different rates, as evidenced by Horvath’s
algorithm, which determines a person’s biological age with greater accuracy than chronological age
based on a specific DNA methylation pattern at 353 selected CpG sites in the genome (Horvath,
2013). Unlike the epigenetic clock, which broadly reflects the general aging process, epigenetic drift is
a unique collection of all acquired changes related to the environment in which an individual or cell
culture ages. Some parts of this mechanism are common across all tissues, but it is known that each
tissue can have its specific mechanisms (Hannum’s epigenetic clock) and that during aging, the clock
ticks faster for longer genes compared to shorter ones. Since pluripotent stem cells avoid age-related
changes in DNA methylation, it is believed that reprogramming aged cells could lead to regeneration
(epigenetic rejuvenation), but it is still unclear how to achieve rejuvenation without the risk of dedifferentiation.
The process of brain aging initiates at the cellular level, with distinct types of neurons aging at varying
rates due to differential susceptibility to cellular aging mechanisms. Key alterations in gene regulation
involve those encoding proteins responsible for synaptic function, responses to oxidative stress, and
neuroinflammation (a state of low-grade inflammation due to heightened expression and activation
of inflammasomes [Figure 1] and the secretion of pro-inflammatory cytokines). Alongside epigenetic
modifications, the most significant changes in neuronal gene regulation include genomic instability
(characterized by the accumulation of DNA damage and reduced efficiency of repair mechanisms,
which are hallmarks of aged neurons leading to somatic mutations), alterations in mtDNA (mutations
occur 10-20 times more frequently than in nuclear DNA due to the generation of reactive oxygen
species during oxidative phosphorylation), and changes in the expression of genes associated with
proteostasis, particularly those regulating autophagy and the ubiquitin-proteasome system for tagging
and degrading damaged and misfolded proteins. The endothelial cells of brain capillaries maintain
the integrity of the blood-brain barrier, which protects the brain from pathogens and other harmful
factors. During aging, these cells are among the first to undergo transcriptional changes, likely due to circulating signals. Indeed, heterochronic parabiosis experiments demonstrate that the plasma of aged
mice accelerates the aging of brain capillary endothelial cells, while the plasma of young mice exerts a
rejuvenating effect (Chen et al., 2020). The most significant rejuvenating interventions currently under
investigation include metabolic interventions (metformin, mTOR antagonists, GLP-1R agonists),
the removal of senescent cells, and epigenetic rejuvenation using Yamanaka transcription factors. A
comparative analysis of gene expression in the brains of 19,300 individuals revealed that the primary
“drivers” of brain aging are neuronal insulin resistance in the 40s (notably increased expression of the
insulin-dependent glucose transporter gene GLUT4 and decreased expression of the monocarboxylate
transporter gene MCT2), vascular changes (reduced expression of VEGFR1), and heightened activation
of innate immunity signaling pathways (increased expression of APOE and IL1B genes) (Antal et
al., 2025). Therefore, future interventions targeting genes that are over or underexpressed during aging
could represent a promising strategy for achieving longevity. A metabolic intervention study involving
101 participants demonstrated that ketones have a potent effect on re-stabilizing cortical network
activity, with the maximum effect occurring between the ages of 40-60, suggesting that in midlife, carbohydrate
intake should be reduced, while protein and healthy fat consumption should be increased,
as has been indicated by the results of caloric restriction experiments for years.
Keywords
aging; brain; epigenetic drift; epigenetic clock; regulation of gene expression.
Hrčak ID:
333471
URI
Publication date:
25.6.2025.
Visits: 335 *