Current Aging Science - Volume 11, Issue 3, 2018

The question whether aging is a disease or not, has been asked by many professionals who are involved in the study of age-related degeneration. However, not only an agreement on this remains elusive, but also effective clinical treatments against human aging have not been forthcoming. In this Opinion paper I suggest that the complexity involved in aging is such that we need to remodel our thinking to involve a much more ‘systems-oriented’ approach. I explore four main principles which should be employed by those who are working on finding treatments against agerelated degeneration. First, I discuss the problems encountered in translating laboratory research into effective therapies for humans. Second, I propose that a ‘systems-thinking’ method needs to be more extensively employed, instead of relying exclusively on the current reductionist one. Third, it is submitted that we must learn from the history of life-extension research, and not blindly follow contemporary paradigms, which may lead us into yet more ‘dead ends’ with regards to therapies. Finally, I suggest that, we may need to employ certain universal notions and use these in order to gain insights into the mechanics of a possible therapy against age-related degeneration. Examples may be the principle of hormesis, those of degeneracy, exaptation, and others from cybernetic or systems science domains. By using this four-pronged approach we liberate our thinking from the shackles of existing common mistakes and fallacies, and we open the way for a fresh approach that may lead us towards entirely new paradigms for providing clinically effective therapies against agerelated degeneration.

Background: Dual-task procedures are commonly implemented to examine cognitive load and listening effort as individual differences in cognition often determine successful listening. However, which methods are most efficacious is unclear. Specifically, standardized, targeted assessment procedures for establishing cognitive function, and age-related changes that might account for changes in dual-task performance have yet to be established. Additional data are needed across aging populations, including middle-aged adults and older adults to establish the trend of performance changes throughout the aging process. Investigations of the relationship between cognitive function and dual-task performance may better inform clinical decisions. Objective: The purpose of this study was to investigate if cognitive function predicts dual-task performance across adults with and without hearing loss. Methods: Participants were divided into two groups based on age. Group 1: 14 listeners (Female = 11), 30-50 years old, with normal hearing. Group 2: 12 listeners (Female = 9), 60-80 years old, with normal hearing to near-normal hearing, including typical age-related hearing loss. Participants were administered four of the Woodcock-Johnson III cognitive subtests and standard hearing threshold procedures. All participants were tested in each of three experimental conditions, including two perceptual-cognitive dual-tasks: (1) Auditory word recognition + visual processing, (2) Auditory working memory (sentence) + visual processing in noise, and (3) Auditory working memory (word) + visual processing. Results: Results indicated that cognitive function does predict dual-task performance regardless of age and hearing function. Conclusion: Cognitive function may predict dual-task performance during speech-in-noise tasks. Further research investigating the predictive value of related cognitive subtests to listening effort is warranted.

Background: During aging, muscle tissue undergoes profound changes which lead to a decline in its functional and regenerative capacity. We utilized global gene expression analysis and gene set enrichment analysis to characterize gene expression changes in aging muscle satellite cells. Method: Gene expression data; obtained from Affymetrix Mouse Genome 430 2.0 Array, for 14 mouse muscle satellite cell samples (5 young, 4 middle-aged, and 5 aged), were retrieved from public Gene Expression Omnibus repository. List of differentially expressed genes was generated based on 0.05 multiple-testing-adjusted p-value and 2-fold FC cut-off values. Functional profiling of genes was carried out using PANTHER Classification System. Results: We have found several differentially expressed genes in satellite cells derived from aged mice compared to young ones. The gene expression changes increased progressively with time, and the majority of the differentially expressed genes were upregulated during aging. While the downregulated genes could not be correlated with specific biological processes the upregulated ones could be associated with muscle differentiation-, inflammation- or fibrosis-related processes. The latter two processes encompass the senescence-associated secretory phenotype for satellite cells which alters the tissue microenvironment and contributes to inflammation and fibrosis observed in aging muscle. Conclusion: Our analysis reveals that by altering gene expression pattern and expressing inflammatory mediators and extracellular matrix components, these cells can directly contribute to muscle wasting in aged mice.

Introduction: Alzheimer's Disease (AD) is a progressive neurodegenerative condition in which individuals exhibit memory loss, dementia, and impaired metabolism. Nearly all previous single-treatment studies to treat AD have failed, likely because it is a complex disease with multiple underlying drivers contributing to risk, onset, and progression. Here, we explored the efficacy of a multi-therapy approach based on the disease risk factor status specific to individuals with AD diagnosis or concern. Methods: Novel software from uMETHOD Health was designed to execute a precision-medicinebased approach to develop personalized treatment recommendations with the goal of slowing or reversing biologic drivers of AD. AD-associated inputs encompassed genomic data, bio-specimen measurements, imaging data (such as MRIs or PET scans), medical histories, medications, allergies, co-morbidities, relevant lifestyle factors, and results of neuropsychological testing. Algorithms were then employed to prioritize physiologic and lifestyle states with the highest probability of contributing to disease status, and these priorities were incorporated into a personalized care plan, which was delivered to physicians and supported by health coaches to increase adherence. The sample included 40 subjects with Subjective Cognitive Decline patients (SCD), and Mild Cognitive Impairment Patients (MCI). Results: Software analysis was completed for 40 individuals. They remained on their treatment plan for an average of 8.4 months, equal to 2.8 iterations of care plans. 80% of individuals overall showed improved memory function scores or held steady, as measured by standardized cognitive evaluations. Cognitive assessments showed significant improvement in the SCD group (Composite P value .002, Executive P value .01), and the CNS-VS Executive domain showed significant results in the combined group as well (P value .01). There was also biomarker improvement over time observed from the blood panels. 8 out of 12 selected biomarkers showed slight, though statistically non-significant, improvement overall for symptomatic individuals, and 6 out of 12 for the overall population. Only one biomarker, homocysteine, showed significant improvement, though (P values .03, .04, .002). Conclusions: Our analysis of these individuals lead to several interesting observations together suggesting that AD risk factors comprise a network of interlocking feedback loops that may be modifiable. Our findings indicate previously unidentified connectivity between AD risk factors, suggesting that treatment regimens should be tailored to the individual and multi-modal to simultaneously return several risk factors to a normative state. If successfully performed, the possibility to slow progression of AD and possibly reverse aspects of cognitive decline may become achievable.

Background: Cognitive frailty emerges as one of the threats to healthy aging. It is in continuum with advancing of age with uncertain indicator between pathological and physiological changes. Alterations in pathways associated with the aging process have been observed including oxidative stress, lipid metabolism, and inflammation. However, the exact mechanisms leading to cognitive decline are still unclear. Objective: This study was sought to assess the level of cognitive functions and linked with blood oxidative status during normal aging in rats. Methods: A longitudinal study using male Sprague Dawley rats was performed starting from the age of 14 months old to 27 months old. Cognitive functions tests such as open field, Morris water maze and object recognition were determined at the age of 14, 18, 23, and 27 months old and were compared with group 3 months old. Blood was collected from the orbital venous sinus and oxidative status was determined by measuring the level of DNA damage, lipid peroxidation, protein oxidation and antioxidant enzymes activity. Results: Aged rats showed declining exploratory behavior and increased in the level of anxiety as compared to the young rats. The level of DNA damage increased with increasing age. Interestingly, our study found that both levels of malondialdehyde and plasma carbonyl content decreased with age. In addition, the level of superoxide dismutase activity was significantly decreased with age whereas catalase activity was significantly increased from 18 months of age. However, no significant difference was found in glutathione peroxidase activity among all age groups. Conclusion: The progressions of cognitive impairment in normal aging rats are linked to the increment in the level of DNA damage.

Introduction: Doege-Potter Syndrome (DPS) is a rare but life-threatening paraneoplastic syndrome, characterized by Non-Islet Cell Tumor-Induced Hypoglycemia (NICTH) secondary to a Solitary Fibrous Tumor (SFT), which secretes an incompletely processed form of Insulin-like Growth Factor 2 (IGF-2). Results: A 96-year-old woman was admitted with head trauma due to an accidental fall. During her hospital stay she experienced frequent hypoglycemic episodes. Multiple injections of 33% dextrose and continuous infusion with 10% dextrose were required to maintain normal blood glucose levels. Biochemical analyses revealed hypoinsulinemic hypoglycemia, low C-peptide levels, suppressed insulin-like growth factor-1, normal insulin-like growth factor-2, and an elevated IGF-2:IGF-1 ratio, all consistent with IGF-2 secretion by a non-islet cell tumor. A contrast-enhanced chest and abdominal CT scans showed a single large pleural mass in the left lower hemithorax measuring 15x14 cm without secondary lesions. Histological analysis of biopsied specimens suggested a solitary fibrous pleural tumor; accordingly, a diagnosis of Doege-Potter syndrome was considered. Due to extensive tumor burden and the advanced age of the patient, supportive and non-invasive management was chosen. Dexamethasone therapy was started, and while receiving this therapy she was able to discontinue glucose infusion and successfully maintain euglycemia. Discussion: In the elderly, a sudden and unexplained fall can be the expression of severe hypoglycemia, usually as a complication of insulin therapy or of oral hypoglycemic agents administered to patients with diabetes. However, in patients without diabetes, other causes should be investigated, and the hypothesis of neoplastic diseases should be considered. Conclusion: In this case report we describe an uncommon cause of paraneoplastic hypoglycemia occurring in the oldest patient with a non-islet cell tumor reported thus far.