As life expectancy across the world increases, there is an increase in the geriatric population, and subsequently, in the prevalence of age-related cognitive failure. The most common culprit for this is Alzheimer’s Disease (AD), which can affect individuals as early as 30 years of age, and its progression can neither be stopped nor slowed. This can have drastic consequences on memory, thinking, behavior, and even personal relationships, which is an incredibly devasting experience for the person themselves and their loved ones who witness this mental decline. The manifestations of this disease are unkind to its possessor and cause disruptions within everyday life. Because of this, the research focused on cognitive aging has significant implications not only in the overall understanding of the process of human aging but also in the formulation of clinical treatments for age-related cognitive disorders.
To uncover the genetic factors linked to cognitive aging, in the article, “Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging,” by Kaczorowski et. al, subjected a genetically diverse cohort of mice to contextual fear conditioning, from which freezing time indicated the existence of contextual fear memory. The contextual fear memory amongst the group of mice was found to be highly variable due to the different genetic factors. From this, interval mapping highlighted a region of chromosome 4, specifically, heterochromatin protein 1 binding protein 3 (Hp1bp3) as being the best candidate for regulating contextual fear memory. Kaczorowski et al. also employed forward and reverse murine genetic approaches in humans and mice cohorts, which revealed that there is a decrease in Hp1bp3 protein levels within the hippocampi of cognitively impaired elderly humans and was found to be associated with memory deficits. Thus, implicating Hp1bp3 with having a significant functional role in cognitive aging and could be associated with the cognitive deficits evident in AD. Notably, metformin hydrochloride, a common drug known to treat symptoms of Type 2 diabetes, also has the ability to upregulate many genes, including Hp1bp3, and therefore, may serve as a potential future treatment for the cognitive decline related to aging.
In addition to Hp1bp3, other mechanisms linked to cognitive aging and its associated dysfunctions have been at the forefront of research, particularly since impaired cerebrovascular function during the aging process is one of the earliest markers of AD. For instance, in the article, “mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging,” from Skike et al, these researchers employed the aid of the Morris water maze and MRI‐based functional imaging in conjunction with biochemical and immunohistochemical approaches to examine the possible contributions of the mechanistic target of rapamycin (mTOR) on the hippocampal‐dependent spatial learning and memory of adult and aged rats. From this, they learned that the chronic attenuation of mTOR resulted in improvements in spatial learning and memory, seemingly because the inhibition allowed for the preservation of synaptic integrity, neuronal network activation, restoration of microvascular integrity, and cerebrovascular function. This may indicate that mTOR not only drives age-related cerebrovascular dysfunction, and but may also have strong associations to AD. Because of this, inhibitors of the mTOR pathways show potential in delaying the progression of AD.
Through the usage of animal models to uncover the complexity of human aging, there is potential to understand not only the body’s natural processes but also its linked disorders and diseases. From the research by Dr. Kaczorowski and Dr. Skike, there is strong evidence to suggest that the aging process is modulated by at least two important proteins, but there is much more to be discovered. Remarkably, both Hp1bp3 and mTOR have the potential to be therapeutic targets in combating age-related deficits, particularly those related to AD. With many medications already in preclinical trials, there is hopefully a treatment in the near future that will enable the progression of this disease to be slowed or perhaps even entirely prevented.
References
Neuner, S. M., Garfinkel, B. P., Wilmott, L. A., Ignatowska-Jankowska, B. M., Citri, A., Orly, J., Lu, L., Overall, R. W., Mulligan, M. K., Kempermann, G., Williams, R. W., O'Connell, K. M., & Kaczorowski, C. C. (2016). Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging. Neurobiology of aging, 46, 58–67. https://doi.org/10.1016/j.neurobiolaging.2016.06.008
Van Skike, C. E., Lin, A. L., Roberts Burbank, R., Halloran, J. J., Hernandez, S. F., Cuvillier, J., Soto, V. Y., Hussong, S. A., Jahrling, J. B., Javors, M. A., Hart, M. J., Fischer, K. E., Austad, S. N., & Galvan, V. (2020). mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging. Aging cell, 19(1), e13057. https://doi.org/10.1111/acel.13057
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