Effect of caloric restriction and rapamycin on ovarian aging in mice Abstract Caloric restriction (CR) increases the preservation of the ovarian primordial follicular reserve, which can potentially delay menopause. Rapamycin also increases preservation on the ovarian reserve, with similar mechanism to CR. Therefore, the aim of our study was to evaluate the effects of rapamycin and CR on metabolism, ovarian reserve, and gene expression in mice. Thirty-six female mice were allocated into three groups: control, rapamycin-treated (4 mg/kg body weight every other day), and 30% CR. Caloric restricted females had lower body weight (P < 0.05) and increased insulin sensitivity (P = 0.003), while rapamycin injection did not change body weight (P > 0.05) and induced insulin resistance (P < 0.05). Both CR and rapamycin females displayed a higher number of primordial follicles (P = 0.02 and 0.04, respectively), fewer primary, secondary, and tertiary follicles (P < 0.05) and displayed increased ovarian Foxo3a gene expression (P < 0.05). Despite the divergent metabolic effects of the CR and rapamycin treatments, females from both groups displayed a similar increase in ovarian reserve, which was associated with higher expression of ovarian Foxo3a.

Heterogeneity of healthy aging: comparing long-lived families across five healthy aging phenotypes of blood pressure, memory, pulmonary function, grip strength, and metabolism Abstract Five healthy aging phenotypes were developed in the Long Life Family Study to uncover longevity pathways and determine if healthy aging across multiple systems clustered in a subset of long-lived families. Using blood pressure, memory, pulmonary function, grip strength, and metabolic measures (body mass index, waist circumference and fasting levels of glucose, insulin, triglycerides, lipids, and inflammatory markers), offspring were ranked according to relative health using gender-, age-, and relevant confounder-adjusted z-scores. Based on our prior work, families met a healthy aging phenotype if ≥ 2 and ≥ 50% of their offspring were exceptionally healthy for that respective phenotype. Among 426 families, only two families met criteria for three healthy aging phenotypes and none met criteria for four or more healthy aging phenotypes. Using Spearman correlation, the proportion of offspring within families with exceptionally healthy pulmonary function was correlated with the proportion of offspring within families with exceptional strength (r = 0.19, p = 0.002). The proportion of offspring within families meeting the healthy blood pressure and metabolic phenotypes were also correlated (r = 0.14, p = 0.006), and more families were classified as meeting healthy blood pressure and metabolic phenotypes (Kappa = 0.10, p = 0.02), as well as the healthy pulmonary and blood pressure phenotypes than expected by chance (Kappa = 0.09, p = 0.03). Other phenotypes were weakly correlated (|r| ≤ 0.07) with low pairwise agreement (Kappa ≤ 0.06). Among these families selected for familial longevity, correspondence between healthy aging phenotypes was weak, supporting the heterogeneous nature of longevity and suggesting biological underpinnings of each individual phenotype should be examined separately to determine their shared and unique determinants.

Important regulatory function of transient receptor potential ankyrin 1 receptors in age-related learning and memory alterations of mice Abstract Expression of the transient receptor potential ankyrin 1 (TRPA1) receptor has been demonstrated not only in the dorsal root and trigeminal ganglia but also in different brain regions (e.g., hippocampus, hypothalamus, and cortex). However, data concerning their role in neurodegenerative and age-related diseases of the CNS is still indistinct. The aim of our study was to investigate the potential role of TRPA1 in a mouse model of senile dementia. For the investigation of changes during aging, we used male young (3–4-month-old) and old (18-month-old) wild-type (TRPA1+/+;WT) and TRPA1 receptor gene-deleted (TRPA1−/−) mice. Novel object recognition (NOR) test as well as Y maze (YM), radial arm maze (RAM), and Morris water maze (MWM) tests were used to assess the decline of memory and learning skills. In the behavioral studies, significant memory loss was detected in aged TRPA1+/+ mice with the NOR and RAM, but there was no difference measured by YM and MWM tests regarding the age and gene. TRPA1−/−showed significantly reduced memory loss, which could be seen as higher discrimination index in the NOR and less exploration time in the RAM. Furthermore, young TRPA1−/− animals showed significantly less reference memory error in the RAM and notably higher mobility in NOR, RAM, and YM compared with the age-matched WTs. Our present work has provided the first evidence that TRPA1 receptors mediate deteriorating effects in the old age memory decline. Understanding the underlying mechanisms could open new perspectives in the pharmacotherapy of dementia.

An expanding GSK3 network: implications for aging research Abstract The last few decades of longevity research have been very exciting. We now know that longevity and healthspan can be manipulated across species, from unicellular eukaryotes to nonhuman primates, and that while aging itself is inevitable, how we age is malleable. Numerous dietary, genetic, and pharmacological studies now point to links between metabolism and growth regulation as a central aspect in determining longevity and, perhaps more importantly, health with advancing age. Here, we focus on a relatively new player in aging studies GSK3, glycogen synthase kinase, a key factor in growth and metabolism whose name fails to convey the extensive breadth of its role in cellular adaptation. First, we provide a brief overview of GSK3, touching on those aspects that are likely relevant to aging. Then, we outline the role of GSK3 in cellular functions including growth signaling, cell fate, and metabolism. Next, we describe evidence demonstrating a direct role for GSK3 in a range of age-related diseases, despite the fact that they differ considerably in their etiology and pathology. Finally, we discuss the role that GSK3 may play in normative aging and how GSK3 might be a suitable target to oppose age-related disease vulnerability.

Genetic conversion of proliferative astroglia into neurons after cerebral ischemia: a new therapeutic tool for the aged brain? Abstract Ischemic stroke represents the 2nd leading cause of death worldwide and the leading cause for long-term disabilities, for which no cure exists. After stroke, neurons are frequently lost in the infarct core. On the other hand, other cells such as astrocytes become reactive and proliferative, disrupting the neurovascular unit in the lesioned area, especially in the aged brain. Therefore, restoring the balance between neurons and nonneuronal cells within the perilesional area is crucial for post stroke recovery. In addition, the aged post stroke brain mounts a fulminant proliferative astroglial response leading to the buildup of gliotic scars that prevent neural regeneration. Therefore, “melting” glial scars has been attempted for decades, albeit with little success. Alternative strategies include transforming inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth by genetic conversion of astrocytes into neurons. The latter idea has gained momentum following the discovery that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming nonneuronal cells into neurons. This exciting new technology emerged as a new approach to circumvent cell transplantation for stroke therapy. However, the potential of this new methodology has not been yet tested to improve restoration of structure and function in the hostile environment caused by the fulminant inflammatory reaction in the brains of aged animals.

Lipotoxicity, aging, and muscle contractility: does fiber type matter? Abstract Sarcopenia is a universal characteristic of the aging process and is often accompanied by increases in whole-body adiposity. These changes in body composition have important clinical implications, given that loss of muscle and gain of fat mass are both significantly and independently associated with declining physical performance as well as an increased risk for disability, hospitalizations, and mortality in older individuals. This increased fat mass is not exclusively stored in adipose depots but may become deposited in non-adipose tissues, such as skeletal muscle, when the oxidative capacity of the adipose tissue itself is exceeded. The redistributed adipose tissue is thought to exert detrimental local effects on the muscle environment given the close proximity. Thus, sarcopenia observed with aging may be better defined in the context of loss of muscle quality rather than loss of muscle quantity per se. In this perspective, we briefly review the age-related physiological changes in cellularity, secretory profiles, and inflammatory status of adipose tissue which drive lipotoxicity (spillover) of skeletal muscle and then provide evidence of how this may affect specific fiber type contractility. We focus on biological contributors (cellular machinery) to contractility for which there is some evidence of vulnerability to lipid stress distinguishing between fiber types.

Systemic milieu and age-related deterioration Abstract Aging is a fundamental biological process accompanied by a general decline in tissue function and an increased risk for age-related disease. The risk for cardiovascular, stroke, cancer, and neurodegenerative diseases significantly increases with aging, especially in people aged 60 years and older in the USA. Although the cellular and molecular mechanisms underlying aging and age-related disease are beginning to be unraveled, the role of the systemic milieu remains unknown. Recent studies have shown that systemic factors in young blood can revise age-related impairments and extend organismal lifespan, suggesting that the systemic milieu contains pro-aging and rejuvenating factors that play a critical role in the health and aging phenotype. In this review, we summarize the current knowledge of systemic milieu changes during the aging process and its link to age-related deterioration.

Genomic instability and innate immune responses to self-DNA in progeria Abstract In the last decade, we have seen increasing evidence of the importance of structural nuclear proteins such as lamins in nuclear architecture and compartmentalization of genome function and in the maintenance of mechanical stability and genome integrity. With over 400 mutations identified in the LMNA gene (encoding for A-type lamins) associated with more than ten distinct degenerative disorders, the role of lamins as genome caretakers and the contribution of lamins dysfunction to disease are unarguable. However, the molecular mechanisms whereby lamins mutations cause pathologies remain less understood. Here, we review pathways and mechanisms recently identified as playing a role in the pathophysiology of laminopathies, with special emphasis in Hutchinson Gilford Progeria Syndrome (HGPS). This devastating incurable accelerated aging disease is caused by a silent mutation in the LMNA gene that generates a truncated lamin A protein “progerin” that exerts profound cellular toxicity and organismal decline. Patients usually die in their teens due to cardiovascular complications such as myocardial infarction or stroke. To date, there are no efficient therapies that ameliorate disease progression, stressing the need to understand molecularly disease mechanisms that can be targeted therapeutically. We will summarize data supporting that replication stress is a major cause of genomic instability in laminopathies, which contributes to the activation of innate immune responses to self-DNA that in turn accelerate the aging process.

Following of aging process in a new motor skill learning model, “pot jumping” in rats Abstract Impairment of procedural memory is a frequent and severe symptom in many neurological and psychiatric diseases as well as during aging. Our aim was to establish an assay in rats in which procedural learning and changes in performance can be studied on the long term. The work was done in the frame of a larger project aiming to establish a complex cognitive animal test battery of high translational value. The equipment was a 190-cm-diameter circular water tank where 12 flower pots were placed upside down in a circle with increasing distances (18–46 cm) between the adjacent ones. Male Lister Hooded and Long-Evans rats were allowed to move on the pots for 3 min. The arena was filled with shallow water to make the rats stay on the pots. Animals were obviously motivated to move around on the pots; however, the distance which required jumping (> 26 cm) meant a barrier for some of them. Development of motor skill was measured by the longest distance successfully spanned. A relatively flat bell-shaped age dependence was observed, with a peak at 13 months of age. A gradual decline in performance could be observed after the age of 20 months which preceded the appearance of overt physical weakness. Long-Evans rats showed more homogeneous performance and higher individual stability than Lister Hooded rats. The method is appropriate to study the development of motor learning and to follow its age-dependent changes. It may also serve as an assay for testing potential drugs for improving motor skills and/or procedural memory.

Age-related impairment of neurovascular coupling responses: a dynamic vessel analysis (DVA)-based approach to measure decreased flicker light stimulus-induced retinal arteriolar dilation in healthy older adults Abstract Aging is a major risk factor for vascular cognitive impairment and dementia (VCID). Recent studies demonstrate that cerebromicrovascular dysfunction plays a causal role in the development of age-related cognitive impairment, in part via disruption of neurovascular coupling (NVC) responses. NVC (functional hyperemia) is responsible for adjusting cerebral blood flow to the increased energetic demands of activated neurons, and in preclinical animal models of aging, pharmacological restoration of NVC is associated with improved cognitive performance. To translate these findings, there is an increasing need to develop novel and sensitive tools to assess cerebromicrovascular function and NVC to assess risk for VCID and evaluate treatment efficacy. Due to shared developmental origins, anatomical features, and physiology, assessment of retinal vessel function may serve as an important surrogate outcome measure to study neurovascular dysfunction. The present study was designed to compare NVC responses in young (< 45 years of age; n = 18) and aged (> 65 years of age; n = 11) healthy human subjects by assessing flicker light-induced changes in the diameter of retinal arterioles using a dynamic vessel analyzer (DVA)-based approach. We found that NVC responses in retinal arterioles were significantly decreased in older adults as compared with younger subjects. We propose that the DVA-based approach can be used to assess NVC, as a surrogate cerebromicrovascular outcome measure, to evaluate the effects of therapeutic interventions in older individuals.