Biological Aging: A Genetic Study

Introduction
Aging is a deleterious, progressive and irreversible cascade of changes in an organism. In humans, biological aging falls under two categories of theories: the programmed aging and the damage theories. Programmed aging theories include the programming of genes, hormones and the immune system to regulate aging, while the damage theories concern free radicals and wear and tear (Jin, 2010). Damage to molecules, cells and organs always accompany aging, resulting in age-related diseases. Current research focuses on treating aging, to bring about longevity and healthy lifestyles. The nematode Caenorhabditis elegans is used as a model organism for genetic studies of aging and longevity.
Caenorhabditis elegans is a free-living bacteriovorus
roundworm found in temperate soils. It is an unsegmented pseudocoelomate and measures about 1 mm. C. elegans reproduces primarily through hermaphrodites while males occur at a low frequency. C. elegans shares the same organ systems with higher animals but lacks a circulatory and a respiratory system. It is the first multicellular organism to have its whole genome sequenced. Moreover, embryogenesis and morphogenesis are fully mapped. These unique features, in addition to having a short life span of 2-3 weeks and easy propagation methods, make C. elegans a model to solve most of the biological mysteries, including aging (Tissenbaum, 2015). C. elegans has different life span controlling pathways of which the insulin-like signaling cascade is a key pathway.
The insulin/IGF-1 signaling (IIS) pathway in C.
elegans mediates diverse metabolic functions related to aging, like heat stress (Lithgow et al., 1995) and oxidative stress responses (Honda and Honda, 1999). Several genes code for the proteins in the IIS. daf-2 and daf-16 are targeted in this review. daf-16, also called Forkhead-type transcription factor, is downregulated by the IIS under stress such as crowding and starvation (Kenyon et al., 1993). This negative regulation is caused by daf-2, which codes for a cell surface receptor (Ogg et al., 1997). daf-16 has a subcellular location and undergoes nucleocytoplasmic shuttling. daf-16 is expressed in the cytoplasm and is activated when it is in the nucleus (Henderson and Johnson, 2001). Its target groups include phosphatases, kinases and transcription factors which play a role in signaling and gene regulation (Murphy, 2006). FKHRL1, now known as FOXO3A, is the human ortholog of daf-16 (Lee et al.,
2001). daf-16 has orthologs in higher animals and the IIS pathway is evolutionarily conserved. This allows comparisons with similar pathways and genes in humans. The need for more information, combined with the vast knowledge on C. elegans, could lead to a cure in humans for age-related and neurodegenerative diseases.
The objective of this review is to analyze recent research published on the factors that regulate daf-16 and its targets, and the similarity to the mechanisms involved in human aging.
The review targets researchers and addresses the progress towards the possible treatment and cure for aging and related diseases. The research papers referred to for this review resulted from a search of the online databases Scopus and Google Scholar, using the keywords ‘C. elegans’, ‘aging’, ‘daf-16’, ‘daf-2’. The papers date from 2008 and onwards. The review focuses initially on a short history of the daf-2 and daf-16 genes. The second section will be about the targets and the various isoforms of daf-16. The third section briefs on the homologs of daf-16 in mammals, focusing specifically on humans. The last section will describe some everyday compounds that regulate daf-16 and about probable research in the search for a
cure.