Age-associated Functional Decline Research Articles

It takes two to tango: NAD+ and sirtuins in aging/longevity control.

The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called ‘sirtuins.’ This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control.

Developmental Origin of Oligodendrocyte Lineage Cells Determines Response to Demyelination and Susceptibility to Age-Associated Functional Decline.

SummaryOligodendrocyte progenitors (OPs) arise from distinct ventral and dorsal domains within the ventricular germinal zones of the embryonic CNS. The functional significance, if any, of these different populations is not known. Using dual-color reporter mice to distinguish ventrally and dorsally derived OPs, we show that, in response to focal demyelination of the young adult spinal cord or corpus callosum, dorsally derived OPs undergo enhanced proliferation, recruitment, and differentiation as compared with their ventral counterparts, making a proportionally larger contribution to remyelination. However, with increasing age (up to 13 months), the dorsally derived OPs become less able to differentiate into mature oligodendrocytes. Comparison of dorsally and ventrally derived OPs in culture revealed inherent differences in their migration and differentiation capacities. Therefore, the responsiveness of OPs to demyelination, their contribution to remyelination, and their susceptibility to age-associated functional decline are markedly dependent on their developmental site of origin in the developing neural tube.

Stem Cell Replicative Stress and Clonal Exhaustion

In humans, the process of aging is characterized by a gradual decline in the functional capacity of multiple tissues, either directly precipitating age-associated diseases or increasing the risk of an individual developing disease, such as in the case of persistent infections or cancer. In regenerating organs, the process of aging is likely driven by the progressive depletion of adult stem cell populations that are responsible for maintaining tissues throughout the lifetime of an organism. One mechanism thought to be a primary cause of progressive adult stem cell depletion with ongoing time, is the accumulation of DNA damage in the stem cell compartment and the subsequent response to this insult. As well as potentially driving the loss of adult stem cells, DNA damage in this cell population is the likely mechanism behind the sequential acquisition of transforming mutations that lead to malignant transformation. Critically, to date, no one has identified the universal physiologic source of DNA damage in adult stem cells that leads to age-associated functional decline and transformation. An in depth interrogation of the mechanism via which adult stem cells acquire DNA damage under physiologic conditions and subsequently respond to this insult is therefore warranted in order to understand the aging process and how this is a critical factor in determining risk of developing cancer and other age-associated diseases. Historically, almost all studies of DNA damage and it's relevance to aging of stem cells either compare young versus aged cells and/or characterize the DNA damage response to artificial experimental agonists such as ionizing radiation, chemotherapy, serial bone marrow transplantation or in vitro culture. Although these approaches have been valuable in furthering our understanding of the relationship between DNA damage and stem cell biology, their physiologic relevance is debatable. The comparison of young versus aged cells assesses the consequences of cellular aging as opposed to the cause of aging, and non-physiologic experimental conditions of DNA damage evaluate a cellular response to an agonist of a type and magnitude that adult stem cells are unlikely to encounter in a normal lifetime. We have recently developed an in vivo model of DNA damage in hematopoietic stem cells (HSCs), which is precipitated by exposure of mice to agonists that mimic physiologic stress such as infection and chronic blood loss. These stress agonists drive HSCs out of their homeostatic quiescent status, resulting in de novo DNA damage as a consequence of increased replicative stress associated with dynamic changes in HSC energy metabolism. Importantly, this stress-induced DNA damage results in a phenotype of cumulative HSC attrition and a myeloid differentiation bias, which is akin to accelerated aging. In the setting of a clinically relevant mouse model of defective DNA repair (Fanconi anemia), stress hematopoiesis leads to a premature collapse of the entire hematopoietic system, fully recapitulating the progression of this disease in Fanconi anemia patients. Such a model is an ideal platform to study the response of HSCs to physiologic DNA damage and will allow us to better understand how environmental stress stimuli such as infections can impact upon both the rate of aging of tissues and the incidence of malignant transformation. This may have important clinical implications relevant to the study of age-related hematopoietic defects in patients. Disclosures No relevant conflicts of interest to declare.

The role of low-grade inflammation and metabolic flexibility in aging and nutritional modulation thereof: A systems biology approach

Aging is a biological process characterized by the progressive functional decline of many interrelated physiological systems. In particular, aging is associated with the development of a systemic state of low-grade chronic inflammation (inflammaging), and with progressive deterioration of metabolic function. Systems biology has helped in identifying the mediators and pathways involved in these phenomena, mainly through the application of high-throughput screening methods, valued for their molecular comprehensiveness. Nevertheless, inflammation and metabolic regulation are dynamical processes whose behavior must be understood at multiple levels of biological organization (molecular, cellular, organ, and system levels) and on multiple time scales. Mathematical modeling of such behavior, with incorporation of mechanistic knowledge on interactions between inflammatory and metabolic mediators, may help in devising nutritional interventions capable of preventing, or ameliorating, the age-associated functional decline of the corresponding systems.

Declining signal dependence of Nrf2‐MafS‐regulated gene expression correlates with aging phenotypes

Aging is a degenerative process characterized by declining molecular, cell and organ functions, and accompanied by the progressive accumulation of oxidatively damaged macromolecules. This increased oxidative damage may be causally related to an age-associated dysfunction of defense mechanisms, which effectively protect young individuals from oxidative insults. Consistently, older organisms are more sensitive to acute oxidative stress exposures than young ones. In studies on the Drosophila Nrf2 transcription factor CncC, we have investigated possible causes for this loss of stress resistance and its connection to the aging process. Nrf2 is a master regulator of antioxidant and stress defense gene expression with established functions in the control of longevity. Here, we show that the expression of protective Nrf2/CncC target genes in unstressed conditions does not generally decrease in older flies. However, aging flies progressively lose the ability to activate Nrf2 targets in response to acute stress exposure. We propose that the resulting inability to dynamically adjust the expression of Nrf2 target genes to the organism's internal and external conditions contributes to age-related loss of homeostasis and fitness. In support of this hypothesis, we find the Drosophila small Maf protein, MafS, an Nrf2 dimerization partner, to be critical to maintain responsiveness of the Nrf2 system: overexpression of MafS in older flies preserves Nrf2/CncC signaling competence and antagonizes age-associated functional decline. The maintenance of acute stress resistance, motor function, and heart performance in aging flies overexpressing MafS supports a critical role for signal responsiveness of Nrf2 function in promoting youthful phenotypes.

Reprint of “Paradoxical Decrease of an Adipose-Specific Protein, Adiponectin, in Obesity”

Ovarian aging occurs approximately 10 years prior to the natural age-associated functional decline of other organ systems. With the increase of life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Therefore, understanding the causes and molecular mechanisms of ovarian aging is very essential for the inhibition of age-related diseases and the promotion of health and longevity in women. Recently, studies have revealed an association between adipose tissue (AT) and ovarian aging. Alterations in the function and quantity of AT have profound consequences on ovarian function because AT is central for follicular development, lipid metabolism, and hormonal regulation. Moreover, the interplay between AT and the ovary is bidirectional, with ovary-derived signals directly affecting AT biology. In this review, we summarize the current knowledge of the complex molecular mechanisms controlling the crosstalk between the AT and ovarian aging, and further discuss how therapeutic targeting of the AT can delay ovarian aging.

DNA-Damage-Induced Differentiation in Hematopoietic Stem Cells

Aging of hematopoietic stem cells (HSCs) is accompanied by diminished functional potential. Wang et al. now provide evidence for an HSC-specific differentiation checkpoint mediated by the transcription factor BATF, which limits self-renewal of HSCs in response to the accumulation of DNA damage.

Aging of the striatum: mechanisms and interventions

Motor function declines with increasing adult age. Proper regulation of the balance between dopamine (DA) and acetylcholine (ACh) in the striatum has been shown to be fundamentally important for motor control. Although other factors can also contribute to this age-associated decline, a decrease in the concentration and binding potential of the DA D(2) receptor subtype in the striatum, especially in the cholinergic interneurons, are involved in the mechanism. Our studies have shown that gene transfer of the DA D(2) receptor subtype with adenoviral vectors is effective in ameliorating age-associated functional decline of the striatal cholinergic interneurons. These achievements confirm that an age-associated decrease of D(2)R contributes functional alteration of the interaction of DA and ACh in the striatum and demonstrate that these age-associated changes indeed are modifiable.

Functional recovery of the striatal cholinergic system in aged rats by adenoviral vector-mediated gene transfer of dopamine D 2 receptor

We previously reported that the striatal dopamine–acetylcholine (ACh) interaction was affected by the aging process, possibly via a decrease of the striatal D 2R expression. In the current study, the ACh responses to the infusion of 0.1 μM of the D 2R agonist quinpirole were measured with microdialysis techniques after adenoviral vector-mediated gene transfer of D 2R into the striatum of 25-month-old rats. The D 2R gene-transferred rats showed significantly stronger responses of the striatal cholinergic neurons to the infusion of the D 2R agonist than did control vector-transferred rats. The current study suggests that age-associated functional decline with decreased gene expression of the receptor may be restored by intervention.

Growth hormone secretagogues:mechanism of action and use in aging

GH secretagogues present a tool for furthering our understanding of the control of GH secretion, as well as a unique therapeutic opportunity. These compounds activate the receptors of a putative endogenous ligand in the hypothalamus and pituitary. Acting as functional somatostatin antagonists, GH secretagogues potentiate the actions of GHRH on GH secretion, enhancing pulsatile GH secretion. The clinical target of the elderly population presents significant challenges to drug development. Age-related musculoskeletal impairment as a result of muscle wasting (sarcopenia) is not well recognized as a clinical syndrome. In addition, given the inherent day to day variability in function in the "frail" target population as well as the presence of a host of concomitant conditions, the appropriate patient population to be studied remains to be defined, and demonstration of clinically meaningful efficacy may be difficult. It is not clear whether it will be useful to restore to young levels the activity of the GHIGF-I axis in aging. Nevertheless, if beneficial effects on strength, similar to those demonstrated with GH79 can be shown, GH secretagogues could provide a well-tolerated clinical approach for treating or preventing sarcopenia, and perhaps, even forestall the inevitability of age-associated decline in function and independence. Such efficacy would have a great social impact.

Effects of aging and dietary restriction on DNA polymerases: gene expression, enzyme fidelity, and DNA excision repair

Hepatic DNA polymerases isolated from young and old C57BL/6N mice fed ad libitum or calorically restricted differed in chromatographic characteristics, binding affinity for DNA template-primer, specific activity, and fidelity of synthesis. DNA polymerase α total and specific activity declined slightly, while the nucleotide misincorporation frequency increased dramatically, with increased age of the donor animals. A positive correlation was observed between polymerase α specific activity and the affinity of enzyme binding to activated DNA template-primer. Both the age-associated decline in enzyme activity and the decrease in fidelity of synthesis were modified by dietary restriction, with higher specific activity levels and lower misincorporation frequencies for DNA polymerases from dietarily restricted animals compared with ad libitum animals of all ages. Fidelity of both DNA polymerase α and β increased following treatment with the phosphoinositide hydrolysis product inositol-1,4-bisphoshate. The data suggest that dietary restriction could play an important role in decreasing the age-associated decline in function of physiological systems sensitive to decreased or defective DNA synthesis.

Cellular theories of aging as related to the liver.

The age-associated decline in function of several organs, including the liver, may be caused by mechanisms operating on the cellular level. Fibroblasts and several other cell types derived from normal individuals have limited lifespans in culture, and several abnormalities described for senescent cultured fibroblasts also apply to hepatocytes and other cell types obtained from aged organisms. Cellular theories of aging can be divided into two broad and overlapping categories: (a) those that view cell death as an actively programmed developmental process, and (b) those that consider cellular aging to result from a passive accumulation of errors in macromolecules. These theories are not necessarily mutually exclusive, and many of the phenotypic changes in senescent hepatocytes, fibroblasts and other cells are compatible with several different theories. The challenge for the future is to distinguish primary causes from secondary consequences of cellular aging so that rational attempts to intervene in the aging process are possible.