Might Cortical Hyper-Responsiveness in Aging Contribute to Alzheimer’s Disease?

Our goal is to understand the neural basis of functional impairment in aging and Alzheimer’s disease (AD) to be able to characterize clinically significant decline and assess therapeutic efficacy. We used frequency-tagged ERPs to word and motion stimuli to study the effects of stimulus conditions and selective attention. ERPs to word or motion increase when a task-irrelevant 2^nd stimulus is added, but decrease when the task is moved to that 2^nd stimulus. Spectral analyses show task effects on response power without 2^nd stimulus effects. However, phase coherence shows both 2^nd stimulus and task effects. Thus, power and coherence are dissociably modulated by stimulus and task effects. Task-dependent phase coherence successively declines in aging and AD. In contrast, task-dependent spectral power increases in aging, only to decrease in AD. We hypothesize that age-related declines in signal coherence, associated with increased power generation, stresses neurons and contributes to the loss of response power and the development of functional impairment in AD.     

Sleep Counteracts Aging Phenotypes to Survive Starvation-Induced Developmental Arrest in C. elegans

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Aging Brain from a Network Science Perspective: Something to Be Positive About?

To better understand age differences in brain function and behavior, the current study applied network science to model functional interactions between brain regions. We observed a shift in network topology whereby for older adults subcortical and cerebellar structures overlapping with the Salience network had more connectivity to the rest of the brain, coupled with fragmentation of large-scale cortical networks such as the Default and Fronto-Parietal networks. Additionally, greater integration of the dorsal medial thalamus and red nucleus in the Salience network was associated with greater satisfaction with life for older adults, which is consistent with theoretical predictions of age-related increases in emotion regulation that are thought to help maintain well-being and life satisfaction in late adulthood. In regard to cognitive abilities, greater ventral medial prefrontal cortex coherence with its topological neighbors in the Default Network was associated with faster processing speed. Results suggest that large-scale organizing properties of the brain differ with normal aging, and this perspective may offer novel insight into understanding age-related differences in cognitive function and well-being.     

Introduction to the Themed Issue on Human–Animal Interaction and Healthy Human Aging

ABSTRACT

In 2016, the Gerontological Society of America (GSA) developed a research focus on the benefits and potential risks associated with pets among older adults. With the goal of developing a roadmap for human–animal interaction (HAI) research in older people residing in both the community and institutions, GSA convened a workshop of international experts and policy-makers in the fields of aging and HAI. The status of current knowledge was shared on the success factors for healthy aging and the potential challenges (GSA, 2016). Participants considered what roles pets might play in the lives of older adults and their potential to mitigate loneliness, social isolation, and depression, and to enhance mobility and cognitive function. Existing research was shared to provide insights into the ways in which pets can impact older adults and their caregivers and to identify where further research is needed. This paper introduces a series of papers from that meeting, with some additional papers from meeting attendees to expand on the topics covered and provide key perspectives and gaps in information needed, as a foundation for those considering research into this topic. Although HAI/Animal-Assistant Intervention (AAI) research is in its infancy, there is some evidence that pet ownership or animal interaction can have major benefits for many older adults. At the same time, there are some risks to both the pet and the older adult that need to be addressed. Innovative approaches to both AAIs and the ways to overcome challenges are presented in this themed issue of Anthrozoös. Our hope is that the findings from these reviews and reports will stimulate additional work in this area.     

TGF-? Sma/Mab Signaling Mutations Uncouple Reproductive Aging from Somatic Aging

Female reproductive cessation is one of the earliest age-related declines humans experience, occurring in mid-adulthood. Similarly, Caenorhabditis elegans'' reproductive span is short relative to its total life span, with reproduction ceasing about a third into its 15–20 day adulthood. All of the known mutations and treatments that extend C. elegans'' reproductive period also regulate longevity, suggesting that reproductive span is normally linked to life span. C. elegans has two canonical TGF-ß signaling pathways. We recently found that the TGF-ß Dauer pathway regulates longevity through the Insulin/IGF-1 Signaling (IIS) pathway; here we show that this pathway has a moderate effect on reproductive span. By contrast, TGF-ß Sma/Mab signaling mutants exhibit a substantially extended reproductive period, more than doubling reproductive span in some cases. Sma/Mab mutations extend reproductive span disproportionately to life span and act independently of known regulators of somatic aging, such as Insulin/IGF-1 Signaling and Dietary Restriction. This is the first discovery of a pathway that regulates reproductive span independently of longevity and the first identification of the TGF-ß Sma/Mab pathway as a regulator of reproductive aging. Our results suggest that longevity and reproductive span regulation can be uncoupled, although they appear to normally be linked through regulatory pathways.     

Is Hypothalamic GABA Involved in Immune Function in Relation to Dietary Protein During Aging?

Hypothalamic GABAergic activity and immune response in spleen were not significantly changed with the increase of age from 3 to 6 months in adult male albino rats. Further increase of age from 6 to 9 months increased the GABAergic activity and decreased the cell viability in spleen without any change in its T-lymphocyte cytotoxicity. Consumption of low protein diet (LPD) for a short-term period (STP; 7 consecutive days) increased the hypothalamie GABAergic activity without changing the immune response in 3 months old rats. When supplemented for a long-term period (LTP; 30 consecutive days) to 3 months old rats, a reduction of hypothalamie GABAergic activity and the immune response was observed. Intake of high protein diet (HPD) for both STP and LTP increased the GABAergic activity and immune response, but the increase of GABAergic activity in hypothalamus under STP was greater than that observed under LTP. In 6 months old rats consumption of LPD for STP reduced the GABAergic activity without any alteration of its immune response. Long-term supplementation of this LPD to the same age group increased GABAergic activity and the mitotic activity of spleen cells without any alteration of the functional activity of the T-cells in spleen. Consumption of HPD for STP failed to produce any change in hypothalamic GABAergic activity and the immune response of 6 months old rats. Supplementation of HPD for LTP reduced the hypothalamic GABAergic activity and the immune response of the same age group. The reduction in hypothalamic GABAergic activity without any change in the immune response was observed following the supplementation of low protein diet to 9 months old rat for STP. Intake of the LPD for LTP also reduced the hypothalamie GABAergic activity and the mitotic activity of the spleen cells without any alteration of the functional activity of the T-cells in spleen of 9 months old rats. Supplementation of HPD for STP to this aged rat, on the other hand, failed to produced any change in hypothalamic GABAergic activity and the immune response. Intake of HPD for LTP by this aged rats increased the hypothalamie GABAergic activity along with the immune response. The results of this study, thus, suggest that hypothalamic GABAergic activity during aging is an index of immune response and it is modulated following the short- and long-term consumption of protein poor and protein rich diet.     

Does Aging Have a Purpose?

Ideas of proponents and opponents of programmed aging concerning the expediency of this phenomenon for the evolution of living organisms are briefly considered. We think that evolution has no “gerontological” purpose, because the obligate restriction of cell proliferation during the development of multicellular organisms is a factor that “automatically” triggers aging due to the accumulation of various macromolecular lesions in cells as a result of the suppression, or even complete cessation of emergence of new, intact cells. This leads to the “dilution” of stochastic damage (the most important of which is DNA damage) at the level of the entire cellular population. Some additional arguments in favor of the inexpediency of aging for both species and individuals are also listed.     

Aging: miRacles of Longevity?

The inventory of processes that miRNAs regulate has continued to expand since their relatively recent discovery. A new study reveals not only that the expression of miRNAs changes with age, but also that these miRNAs can act?in?both pro- and anti-longevity regulatory pathways.     

Aging: all in the head?

Global reduction in insulin signaling has been linked to extended life span in a range of organisms. New work on mice with brain-specific or whole-body reductions in insulin receptor substrate 2 (IRS2) (Taguchi et al., 2007) points to a role for insulin/IGF-1 signaling in the central control of mammalian aging.     

Aging by epigenetics--a consequence of chromatin damage?

Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.     

Protein Homeostasis, Aging and Alzheimer’s Disease

Alzheimer's disease (AD) is one key medical challenge of the aging society and despite a great amount of effort and a huge collection of acquired data on molecular mechanisms that are associated with the onset and progression of this devastating disorder, no causal therapy is in sight. The two main hypotheses of AD, the amyloid cascade hypothesis and the Tau hypothesis, are still in the focus of AD research. With aging as the accepted main risk factor of the most important non familial and late onset sporadic forms of AD, it is now mandatory to discuss more intensively aspects of cellular aging and aging biochemistry and its impact on neurodegeneration. Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis. This is the purpose of this short review.     

Cognitive Aging: Recapturing the Excitation of Youth?

The electrical excitability of cortical neurons changes significantly during normal ageing. A recent study found that targeted deletion of a gene encoding a potassium channel-modifier subunit can restore to aged mice, not only normal neuronal firing, but also normal learning and synaptic plasticity.     

Increased Oxidative Damage and Decreased Antioxidant Function in Aging Human Substantia Nigra Compared to Striatum: Implications for Parkinson’s Disease

Parkinson’s disease (PD) is characterized by selective degeneration and loss of dopaminergic neurons in the substantia nigra (SN) of the ventral mid brain leading to dopamine depletion in the striatum. Oxidative stress and mitochondrial damage have been implicated in the death of SN neurons during the evolution of PD. In our previous study on human PD brains, we observed that compared to SN, striatum was significantly protected against oxidative damage and mitochondrial dysfunction. To understand whether brain aging contributes to the vulnerability of midbrain to neurodegeneration in PD compared to striatum, we assessed the status of oxidant and antioxidant markers, glutathione metabolic enzymes, glial fibrillary acidic protein (GFAP) expression and mitochondrial complex I(CI) activity in SN (n = 23) and caudate nucleus (n = 24) during physiological aging in human brains. We observed a significant increase in protein oxidation (P < 0.001), loss of CI activity (P = 0.04) and increased astrocytic proliferation indicated by GFAP expression (P < 0.001) in SN compared to CD with increasing age. These changes were attributed to significant decrease in antioxidant function represented by superoxide dismutase (SOD) (P = 0.03), glutathione (GSH) peroxidase (GPx) (P = 0.02) and GSH reductase (GR) (P = 0.03) and a decreasing trend in total GSH and catalase with increasing age. However, these parameters were relatively unaltered in CD. We propose that SN undergoes extensive oxidative damage, loss of antioxidant and mitochondrial function and increased GFAP expression during physiological aging which might make it more vulnerable to neurotoxic insults thus contributing to selective degeneration during evolution of PD.     

Stochastic Simulations of Normal Aging and Werner’s Syndrome

Human cells typically consist of 23 pairs of chromosomes. Telomeres are repetitive sequences of DNA located at the ends of chromosomes. During cell replication, a number of basepairs are lost from the end of the chromosome and this shortening restricts the number of divisions that a cell can complete before it becomes senescent, or non-replicative. In this paper, we use Monte Carlo simulations to form a stochastic model of telomere shortening to investigate how telomere shortening affects normal aging. Using this model, we study various hypotheses for the way in which shortening occurs by comparing their impact on aging at the chromosome and cell levels. We consider different types of length-dependent loss and replication probabilities to describe these processes. After analyzing a simple model for a population of independent chromosomes, we simulate a population of cells in which each cell has 46 chromosomes and the shortest telomere governs the replicative potential of the cell. We generalize these simulations to Werner’s syndrome, a condition in which large sections of DNA are removed during cell division and, amongst other conditions, results in rapid aging. Since the mechanisms governing the loss of additional basepairs are not known, we use our model to simulate a variety of possible forms for the rate at which additional telomeres are lost per replication and several expressions for how the probability of cell division depends on telomere length. As well as the evolution of the mean telomere length, we consider the standard deviation and the shape of the distribution. We compare our results with a variety of data from the literature, covering both experimental data and previous models. We find good agreement for the evolution of telomere length when plotted against population doubling.     

Aging,osteoarthritis and transforming growth factor-β signaling in cartilage

Osteoarthritis is a common malady of the musculoskeletal system affecting the articular cartilage. The increased frequency of osteoarthritis with aging indicates the complex etiology of this disease, which includes pathophysiology and joint stability including biomechanics. The balance between anabolic morphogens and growth factors and catabolic cytokines is at the crux of the problem of osteoarthritis. One such signal is transforming growth factor-β (TGF-β). The impaired TGF-β signaling has been identified as a culprit in old mice in a recent article in this journal. This commentary places this discovery in the context of anabolic and catabolic signals and articular cartilage homeostasis in the joint.