In article “Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging” researcher Catherine Kaczorowski and colleagues look for genetic factors involved in cognitive aging by studying 21 strains of BXD mice. They analyze hippocampal dependent memory function, utilizing freeze time as a measure of contextual fear memory, and find fear memory to be highly variable across the 21 strains due to genetic differences. Interval mapping for each strain highlights a qualitative trait locus on chromosome 4 that is not associated with memory function in younger aged BXD mice. The gene heterochromatin protein 1 binding protein 3 (Hp1bp3) was chosen from this qualitative trait locus as the best candidate for regulating contextual fear memory. Hp1bp3 hippocampal expression is directly correlated with contextual fear memory, as mice with lower Hp1bp3 levels exhibit worse fear memory performance. Furthermore, Hp1bp3 knockout mice exhibit similar performance levels. When examined in humans, a significant decrease in Hp1bp3protein levels is found within the hippocampus of cognitively impaired elderly humans, like those with Alzheimer’s Disease (AD), compared to those who are cognitively intact. In the end, Hp1bp3 is strongly proven to have a significant role in cognitive aging and could extend to the cognitive deficits presented in Alzheimer’s Disease. As such, treatments that restore Hp1bp3 expression could improve cognition in patients with cognitive decline or AD dementia. Such a treatment is metformin hydrochloride, which has shown to increase Hp1bp3 expression as well as enhance memory in mice. The researchers state that metformin has been approved for anti-aging clinical trials in humans.
In the article “Metformin and Its Benefits for Various Diseases” Ziguan Lv and Yajie Guo go over the possible underlying mechanisms of metformin towards its many benefits. Other studies have shown that metformin has a “strong effect on numerous cancers, cardiovascular diseases, liver diseases, obesity, neurodegenerative diseases, and renal diseases.” In diabetes, metformin has shown to be dose dependent, easily compatible with other drugs, and safer for diabetic pregnant women. Metformin aids Type II diabetics in at least 5 ways: decreasing liver glucose production, increasing skeletal muscle uptake of glucose, increaseing absorption of glucose in the intestines, and enhancing insulin secretion. Additionally, it may affect gut microbiota as well. In relation to cancer, metformin inhibits growth, survival, and metastasis of tumor cells in 3 ways: activating AMPK, inhibiting mTORC1, and suppressing mitochondrial complex I. Studies have also shown that metformin may activate the body’s immune system response to cancer cells. By decreasing glucose levels, metformin is limiting the energy for cancer cells to perform cellular functions and spread. Metformin also increases the bile acid pool of the intestine, changes the microbiome, and affects metabolism. This effect on metabolism is, in part, why metformin can also be used to decrease obesity. Through AMPK, metformin decreases the occurrence of cardiovascular disease, improves myocardial tissue energy and hypertrophy of the left ventricle of the heart. Other researchers have shown that metformin can improve kidney fibrosis and normalize kidney structure and function through its effect on AMPK. These diseases have a much higher chance of occurring as age increases. As such, metformin is seen as a drug that “improves aging-related diseases” and extends life span.
The effect of metformin hydrochloride on AMPK, AKT, and mTOR is highly influential because of these 3 protein’s involvements in many signaling pathways. All of these proteins are involved in the diseases mentioned previously. By looking at the effects of metformin on the body; the reasons why metformin is such a great diabetic drug, one can see the overlaps in pathways and function between those effects. In doing so, metformin can be used as treatment beyond Diabetes Mellitus. In the study with Kaczorowski et al., metformin’s effect of increasing Hp1bp3 expression is seen as a new possible treatment for cognitive aging. A drug that has been used for over 60 years as an anti-hyperglycemic drug is now being used for cancer as well as numerous diseases. Metformin deserves further research because many of its benefits have yet to be confirmed, and there may be more. Furthermore, it is reasonable to deduce that metformin is not the only drug with such plentiful effects. There is reason to suspect that there are many other drugs that have yet to be utilized to their full potential. Exemplified by metformin, exploring the the pathways of drugs is a worthwhile endeavor in order to realize their full potential.
References
Lv, Ziquan., Guo, Yajie. “Metformin and Its Benefits for Various Diseases.” Frontiers in endocrinology vol. 11 191. 16 Apr. 2020, doi:10.3389/fendo.2020.00191
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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