Despite recent advances in molecular biology and genetics, the mysteries that control human lifespan are yet to be unraveled. Many theories, which fall into two main categories: programmed and error theories, have been proposed to explain the process of aging, but neither of them appears to be fully satisfactory. These theories may interact with each other in a complex way. By understanding and testing the existing and new aging theories, it may be possible to promote successful aging.

Harman’s Free Radical Theory of Aging has been considered as a major theory of aging for more than 50 years. In 1956 Dr. Harman proposed that the accumulation of free radicals with the age causes the damage of biomolecules by these reactive species and the development of pathological disorders resulting in cell senescence and organismal aging. His hypothesis was supported by numerous experimental studies demonstrated an increase in free radical levels in cells and living organisms with aging. In subsequent years important discoveries of new physiological free radicals superoxide and nitric oxide have been made that led to understanding of other important functions of free radicals. It has been shown that superoxide and nitric oxide together with their diamagnetic reaction products hydrogen peroxide and peroxynitrite (all are now named reactive oxygen and nitrogen species, ROS and RNS) function as signaling species in many physiological enzymatic/gene processes. Furthermore, the disturbance of ROS and RNS physiological signaling can be an origin of various pathologies and aging. These discoveries demanded to widen original free radical theory of aging and to consider the damaging ROS signaling as an important, maybe major route to cell senescence and organismal aging. However, some experimental findings such as the extension of lifespan by calorie restriction of yeast, flies, worms, and mice, and favorable effects of physical exercises stimulated criticism of free radical theory because the expansion of lifespan accompanied in some cases by increasing oxidative stress. On these grounds such theories as Hormesis and Target of rapamycin (mTOR) theories refute the role of ROS and oxidative stress in aging. Accordingly, a major purpose of this review to show that ROS signaling is probably the most important enzyme/gene pathway responsible for the development of cell senescence and organismal aging and that ROS signaling might be considered as further development of free radical theory of aging. In spite of apparent contradictions the Hormesis or TOR theories are also describing processes of aging development regulated by ROS signaling.

Dietary restriction (DR) is a robust non-genetic intervention that reduces morbidity and mortality in a range of organisms. This suggests the presence of an evolutionary-conserved pathway that regulates aging and lifespan in response to reduced food or energy intake. Recent genetic analyses have shown that single gene mutations could extend the lifespan, even in mammals. Many longevity genes are clustered into nutrient-sensing and metabolic adaptation pathways, which are also thought to be involved in the effect of DR. The responses of these mutant animals to DR in terms of lifespan or other aging phenotypes suggest that proteins encoded by these genes are involved in the effects of DR. This review focuses on the roles of fork head box O (FoxO) transcription factors, AMP-activated protein kinase (AMPK), and sirtuins (particularly SIRT1) in the effects of DR in rodents. FoxO transcription factors are mammalian orthologs of DAF-16, which is required for the lifespan extending effects of reduced insulin-like signaling in nematodes. A recent study in rodents suggested that FoxO1 is involved in the anti-neoplastic effects of DR. Although aak2 in nematodes (mammalian AMPK), Sir2 in yeast and Sir2.1 in nematodes (mammalian SIRT1) were also reported to be essential for lifespan extension by DR, the findings are thought to depend on the genetic backgrounds of the organisms and/or methods used to induce DR. In rodents, AMPK and SIRT1 are implicated in the metabolic regulation by long-term DR. Genetic and molecular dissection of the mechanisms underlying the effects of DR will provide us with knowledge of the basic aging processes, as well as insights into the development of DR mimetics, to extend the healthy lifespan in humans.

A temporal framework linking circadian rhythms and clocks to aging rates identifies a specific window of target of rapamycin (TOR) signaling associated with growth hormone (GH) and insulin-like growth factor (IGF-1) (largely exclusive of insulin) in early sleep. IGF-1 signaling is released by growth hormone secretory peaks and downregulation of IGF-1 binding protein-1 resulting in activation of the mitogen activated protein kinase/extracellular signal response kinase (MAPK/ERK) and phosphoinositide 3-kinase-protein kinase B (PI3K-PKB/Akt) signaling pathways. Phosphorylation of Akt activates TOR which mediates the protein synthesis and growth functions of the GH axis. TOR activity is also associated with downregulated stress resistance, faster aging and reduced lifespan. IGF-1 signaling is terminated by falling GH and upregulation of IGF-1 binding proteins mediated by somatostatin and rising corticosteroids in later sleep. This suppresses PI3K-Akt signaling, thus activating the forkhead transcription factors (FOXOs) and stress-resistance pathways involved in promoting longevity. Thus, sleep appears to encompass both pathways currently identified as most relevant to aging and they toggle successively on the phosphorylation status of Akt. I propose a modified version of Pearl’s rate of living theory emphasizing the hard-wired antagonism of growth (TOR) and stress resistance (FOXO). The sleep association of TOR and FOXO in temporally separated windows and their sequential temporal deployment may change much of the way we think about aging and how to manipulate it.

In the past couple of centuries, scientists proposed great number of aging theories but neither of them appears to be fully satisfactory. In the statistical sense, we are dealing with an even greater challenge because large array of factors affects the aging process. Although at this point the most of these factors are well known, it is the very fact of their innumerability that complicates approaches to the issue at hand. Both in life and in medicine, the cause behind an effect can rarely be unequivocally determined. Thus, it appears that through out human history longevity has been primarily affected by eradication of diseases, especially by eradication of infectious diseases and introduction of the vaccines. For that reason, maybe we should not be referring to this issue as the «fountain of youth» but rather as the «vaccine of youth». The postulate that genetic instability is the precipitating factor both of aging and cancer has withstood many tests and keeps on being reaffirmed. For this reason, it is legitimate to pose a question of whether long-lived individuals may be those with «selfish» genes and more stable genetic material. They certainly cannot avoid aging, but aging in such individuals could be delayed due to steady character of their genome, which is less susceptible to mutations. On the population level, they constitute minority because stable genome would represent an obstacle to successful evolution of the species. If this was not the case, we might not be writing all these texts today.

It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. Likewise, substantial increases in lifespan are associated with mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1 like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and IGF-2 with different affinities. In several mouse models, mutations that are associated with decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with enhanced lifespan. However, the increased complexity of the mammalian insulin/IGF-1 system has made it difficult to separate the roles of insulin, GH and IGF-1 in mammalian longevity. Likewise, the relevance of reduced insulin and IGF-1 signaling in human longevity remains controversial. However, studies on the genetic and metabolic characteristics that are associated with healthy longevity and old age survival suggest that the conserved ancient IIS pathway may also play a role in human longevity.

The evidence that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) of mammals opens new avenues and opportunities for our understanding of development and for therapy. Newly generated neuronal cells of the adult brain would contribute to the physio-pathology of the nervous system and the adult brain may be amenable to repair. The contribution of adult neurogenesis to the functioning of the nervous system remains to be elucidated and adult NSCs have yet to be brought to therapy. It is generally accepted that NSCs in the adult brain have a regenerative capacity. Yet, evidences suggest that they may also contribute to pathological developments in neurological diseases. Alzheimer’s disease (AD) is a neurodegenerative disease and the hippocampus is one of the regions of the brain the most affected by the disease. AD is characterized by neurodegeneration, amyloid plaques, neurofibrillary tangles, aneuploidy and enhanced neurogenesis in the adult brain. The process of adult neurogenesis holds the potential to generate populations of cells that are aneuploid, particularly in the neurogenic regions. Aneuploid newly generated neuronal cells of the adult brain would contribute to the pathology of AD. Adult neurogenesis would not only contribute to regenerative attempts in the CNS, but also to the pathogenesis of neurological diseases and disorders.