Sirtuins: Developing Innovative Treatments for Aged-Related Memory Loss and Alzheimer’s Disease

Abstract

The world's population continues to age at a rapid pace. By the year 2050, individuals over the age of 65 will account for sixteen percent of the world's population and life expectancy will increase well over eighty years of age. Accompanied with the aging of the global population is a significant rise in non-communicable diseases (NCDs). Neurodegenerative disorders will form a significant component for NCDs. Currently, dementia is the 7 th leading cause of death and can be the result of multiple causes that include diabetes mellitus, vascular disease, and Alzheimer's disease (AD). AD may represent at least sixty percent of these cases. Current treatment for these disorders is extremely limited to provide only some symptomatic relief at present. Sirtuins and in particular, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), represent innovative strategies for the treatment of cognitive loss. New work has revealed that SIRT1 provides protection against memory loss through mechanisms that involve oxidative stress, Aβ toxicity, neurofibrillary degeneration, vascular injury, mitochondrial dysfunction, and neuronal loss. In addition, SIRT1 relies upon other avenues that can include trophic factors, such as erythropoietin, and signaling pathways, such as Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). Yet, SIRT1 can have detrimental effects as well that involve tumorigenesis and blockade of stem cell differentiation and maturation that can limit reparative processes for cognitive loss. Further investigations with sirtuins and SIRT1 should be able to capitalize upon these novel targets for dementia and cognitive loss.

Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm

“…In familial AD that affects 200 families worldwide, mutations in the presenilin 1 or 2 genes occurs and an autosomal dominant mutated amyloid precursor protein (APP) gene exists. In these familial AD patients, illness can present prior to 55 years of age [44][45][46]. Familial AD can be the result of mutations in chromosome 21 leading to changes in APP, mutations in chromosome 14 causing changes in presenilin 1, and mutations in chromosomes 1, 14, and 21 such that mutations in chromosome 1 lead to changes in presenilin 2.…”

“…Current attempts to treat dementia such as with cholinesterase inhibitors may lead to a decrease in the presenting symptoms but ultimately do not block the progression of the disease, such as in AD [27,45,47,48]. Other treatments for cognitive loss can focus on metabolic disorders, such as diabetes mellitus (DM) [1,20,27,41,49,50], and on vascular disease [19,45,[51][52][53].…”

“…Current attempts to treat dementia such as with cholinesterase inhibitors may lead to a decrease in the presenting symptoms but ultimately do not block the progression of the disease, such as in AD [27,45,47,48]. Other treatments for cognitive loss can focus on metabolic disorders, such as diabetes mellitus (DM) [1,20,27,41,49,50], and on vascular disease [19,45,[51][52][53]. Yet, there exist other risks for developing vascular cognitive loss that can affect the efficacy of treatments such as tobacco use, alcohol consumption, hypertension, and a low level of education [20,39,[54][55][56][57].…”

“…Biological clock pathways closely rely upon SIRT1 [6,84,85,91,193,194] (Table 1). SIRT1 is a histone deacetylase that can transfer acetyl groups from ϵ-N-acetyl lysine amino acids to the histones of deoxyribonucleic acid (DNA) to control transcription [19,45,48,84,85,152,[195][196][197][198][199][200]. As noted above, SIRT1 plays a critical role in nervous system diseases [164,199,201,202] that also are dependent upon autophagy regulation [113,178,185,186,190,203].…”

Exercise-Induced Autophagy Suppresses Sarcopenia Through Akt/mTOR and Akt/FoxO3a Signal Pathways and AMPK-Mediated Mitochondrial Quality Control

“…As the population undergoes rapid aging, the number of elderly patients with aging-related diseases is also increasing. By 2050, the number of individuals over 65 years old will increase to over 1.5 billion (Maiese, 2018). Aging and aging-related diseases have become a public health problem with potential threats.…”