As we age, our genetic makeup tends to change and also our abilities to
think. The idea of cognitive aging helps us to understand the effects of aging
and can also help us find an early diagnosis for at-risk patients for diseases
such as Alzheimer’s. As humans, there is more than what makes up who we are
such as complex genetics, the environment, and the continued process of
evolution. However, we can start to look at cognitive aging and what genes and
activities in our brain are needed to diminish the amount of DNA damage and
neural diseases as we age.
In “Systems genetics identifies Hp1bp3 as a novel
modulator of cognitive aging” by Neuner et. al.’s research team, we are
introduced to the importance of Hp1bp3 to cognitive aging, especially
Alzheimer’s disease. Through the study done with mice, it was found that
Hp1bp3, which was identified on an interval on chromosome 4, helped in
hippocampus-dependent memory function across middle-aged mice. To find this
out, they knocked out the Hp1bp3 gene from a group of mice and compared it to
regular adulting mice with the same shock experiment. It was found that the
knockout mice exhibited long-term CFM deficits when tested 24 hours later from
the shock reactivity experiment. Furthermore, Hp1bp3 was known to contain
multiple missense variants in coding regions, many non-coding variants, and
insertions and deletions detailing to have some impact on protein
function. In cognitive aging, Hp1bp3 is important in long-term and
spatial working memory. In humans, it was seen in the study that Hp1bp3 is more
conserved as it does have important roles in human cognition. In the study, the
comparison of hippocampal tissue in humans showed genetic correlation to the
functional roles of Hp1bp3 as was seen in mice. Some of the
functions the study listed were regulation of chromatin structure, gene
expression, cell cycle progression, and insulin signaling. So, the absence of
Hp1bp3 would cause extreme deficits in cognitive aging and can lead to severe
types of neural diseases like Alzheimer’s or dementia.
In another study at the Massachusetts Institute of
Technology, neuroscientists discovered the importance of HDAC1 in cognitive
aging as well. The enzyme HDAC! Is important in repairing age-related DNA
damage to genes involved in memory and other cognitive functions. In this
study, they also used mice and had the wild-type mice with the HDAC1 and a
knockout mice group with a hindered expression of HDAC1. In the beginning, the
mice from both groups looked the same and thought the same. As the mice started
to age, a specific type of DNA damage builds up that resembles what happens in
patients with Alzheimer’s disease. HDAC1 is seen to modify histone proteins
around which DNA is coiled. One of the functions of HDAC1 is that it blocks
genes in certain stretches of DNA from being copied to RNA. When the HDAC1 was
knocked out from the mice and aged, the mice lost some of their ability to act
on synaptic plasticity. Furthermore, the lack of HDAC1 showed impairments in tests
of memory and spatial navigation. The reason I found this study interesting was
that the effect of HDAC1 is similar to some of the damage done to DNA during
Alzheimer’s. In Alzheimer’s disease, one of the DNA damages done is called
8-Oxo-guanine lesions. To prevent these lesions from happening, the use of the
OGG1 gene is needed. However, to activate OGG1 you need the HDAC1 gene. Without
the presence of HDAC1, this type of lesion will build up and cause more damage
to the patient with Alzheimer’s disease. Some of the findings for this study
suggested the use of exifone, which is a type of drug used to help reduce the
DNA damage in mice that model Alzheimer’s disease and regular aging mice.
However, Exifone is not widely used as the side effects seem to be harmful. On
the brighter side, these findings suggest that safer HDAC1-activating drugs
would be worth reducing the damaging DNA build-up from happening.
With these two studies, it is important to notice the
demand for more research for cognitive aging and Alzheimer’s disease. The
expression of genes such as Hp1bp3 and HDAC1 are important to take note of for
future directions of neural diseases. Through the connection of humans and
mice, we are able to see the effects of certain genes in aging adults and how
it defers from “healthy” adults. These studies come to show how there are many
genes that can ultimately be helpful to diminish the damage of cognitive aging
and many other diseases. I hope in more studies and research can we see how
genes that have cognitive functions relate to one another and see the degree of
importance for those genes.
References:
Massachusetts Institute of Technology. "Aging neurons accumulate
DNA damage: Reactivating an enzyme that promotes DNA repair can help to reverse
age-related cognitive decline in mice." ScienceDaily. ScienceDaily, 18 May
2020. <www.sciencedaily.com/releases/2020/05/200518090030.htm>.
Neuner, Sarah M., Kaczorowski, Catherine C., et al. “Systems genetics
identifies Hp1bp3 as a novel modulator of cognitive aging.” Neurobiology of
aging vol. 46 (2016): 58-67. doi:10.1016/j.neurobiolaging.2016.06.008
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