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1.  Errata 
PMCID: PMC4888381  PMID: 26386011
2.  Errata 
PMCID: PMC4888401  PMID: 27059599
3.  Age-Associated Increase in Cytokine Production During Systemic Inflammation—II: The Role of IL-1β in Age-Dependent IL-6 Upregulation in Adipose Tissue 
Expression of interleukin-6 (IL-6) upon acute inflammatory stress is significantly augmented by aging in adipose tissue, a major source of this cytokine. In the present study, we examined the mechanism of age-dependent IL-6 overproduction using visceral white adipose tissue from C57BL/6 mice. Upon treatment with lipopolysaccharide (LPS) in vitro, IL-6 was produced by adipose tissue explants, and secreted levels were significantly higher in cultures from aged (24 months) mice compared to young (4 months). Interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNFα), two inducers of IL-6, were mainly produced by the lungs and spleen rather than adipose tissue in mice after LPS injection. Treatment of adipose explants with physiological levels of IL-1β induced significant age-dependent secretion of IL-6, while treatment with TNFα had little effect, demonstrating an augmented response of adipose tissues to IL-1β in the aged. In vitro experiments utilizing a neutralizing antibody against IL-1β and in vivo experiments utilizing IL-1-receptor-1 deficient mice, confirmed that IL-6 overproduction in the aged is regulated by autocrine/paracrine action of IL-1β which specifically occurs in aged adipose tissues. These findings indicate an elevated inflammatory potential of adipose tissue in the aged and a unique IL-1β-mediated mechanism for IL-6 overproduction, which may impact age-associated vulnerability to acute inflammatory diseases such as sepsis.
PMCID: PMC4643612  PMID: 25344820
Aging; Adipose tissue; IL-6; IL-1β; Inflammation; Sepsis
4.  Antihypertensive Use and Recurrent Falls in Community-Dwelling Older Adults: Findings From the Health ABC Study 
Despite wide-spread use of antihypertensives in older adults, the literature is unclear about their association with incident recurrent falls over time.
Health, Aging and Body Composition study participants (n = 2,948) who were well functioning at baseline (1997) were followed to Year 7 (2004). The main outcome was recurrent falls (≥2) in the ensuing 12 months. Antihypertensive use was examined as: (a) any versus none, (b) long- versus short-term (≥2 vs <2 years), and by (c) summated standardized daily dose (SDD; 1 = maximum recommended daily dose for one antihypertensive), and (d) subclass.
Controlling for potential demographic, health status/behavior and access to care confounders, we found no increase in risk of recurrent falls in antihypertensive users compared to nonusers (adjusted odds ratio [AOR] = 1.13; 95% CI = 0.88–1.46), or those taking higher SDDs or for longer durations. Only those using a loop diuretic were found to have a modest increased risk of recurrent falls (AOR = 1.50; 95% CI = 1.11–2.03).
Antihypertensive use overall was not statistically significantly associated with recurrent falls after adjusting for important confounders. Loop diuretic use may be associated with recurrent falls and needs further study.
PMCID: PMC4643613  PMID: 26265732
Falls; Medication; Epidemiology; Drug related
5.  Frailty, Inflammation, and Mortality Among Persons Aging With HIV Infection and Injection Drug Use 
Serum markers of inflammation increase with age and have been strongly associated with adverse clinical outcomes among both HIV-infected and uninfected adults. Yet, limited data exist on the predictive and clinical utility of aggregate measures of inflammation. This study sought to evaluate the relationship of a recently validated aggregate inflammatory index with frailty and mortality among aging HIV-infected and uninfected injection drug users.
Frailty was assessed among HIV-infected and uninfected participants in the AIDS Linked to the IntraVenous Experience (ALIVE) cohort study using the five Fried phenotypic criteria: weight loss, exhaustion, low physical activity, decreased grip strength, and slow gait. The aggregate inflammatory index was constructed from serum measures of interleukin-6 and soluble tumor necrosis factor-α receptor-1. Multinomial logistic regression was used to assess the relationship of frailty with inflammation. Cox proportional hazards models were used to estimate risk for all-cause mortality.
Among 1,326 subjects, the median age was 48 years and 29% were HIV-infected. Adjusting for sociodemographics, comorbidity, and HIV status, frailty was significantly associated with each standard deviation increase in log interleukin-6 (odds ratio 1.33; 95% CI, 1.09–1.61), log tumor necrosis factor-α receptor-1 (odds ratio 1.25; 95% CI, 1.04–1.51) and inflammatory index score (odds ratio 1.39; 95% CI, 1.14–1.68). Adjusting for sociodemographics, comorbidity, HIV status, and frailty, the inflammatory index score was independently associated with increased mortality (HR 1.65; 95% CI, 1.44–1.89).
A recently validated, simple, biologically informed inflammatory index is independently associated with frailty and mortality risk among aging HIV-infected and uninfected injection drug users.
PMCID: PMC4643614  PMID: 26386010
Frailty; Inflammation; HIV; Mortality; Injection drug use
6.  Aging, the Central Nervous System, and Mobility in Older Adults: Neural Mechanisms of Mobility Impairment 
Mobility is crucial for successful aging and is impaired in many older adults. We know very little about the subtle, subclinical age-related changes in the central nervous system (CNS) that mediate mobility impairment.
A conference series focused on aging, the CNS, and mobility was launched. The second conference addressed major age-associated mechanisms of CNS-mediated mobility impairment. Speakers and conference attendees recommended key areas for future research, identified barriers to progress, and proposed strategies to overcome them.
Priorities identified for future research include (a) studying interactions among different mechanisms; (b) examining effects of interventions targeting these mechanisms; (c) evaluating the effect of genetic polymorphisms on risks and course of age-related mobility impairment; and (d) examining the effect of age on CNS repair processes, neuroplasticity, and neuronal compensatory mechanisms. Key strategies to promote research include (a) establish standard measures of mobility across species; (b) evaluate the effect of aging in the absence of disease on CNS and mobility; and (c) use advanced computational methods to better evaluate the interactions between CNS and other systems involved in mobility.
CNS is a major player in the process, leading to mobility decline with aging. Future research in this area has the potential to prolong independence in older persons. Better interactions among disciplines and shared research paradigms are needed to make progress. Research priorities include the development of innovative approaches to integrate research on aging, cognition, and movement with attention to neurovascular function, neuroplasticity, and neurophysiological reserve.
PMCID: PMC4643615  PMID: 26386013
CNS; Aging; Mobility; Imaging
7.  Assessing Walking Activity in Older Adults: Development and Validation of a Novel Computer-Animated Assessment Tool 
Assessing volume of physical activity (PA) in older adults is critical to understanding the role that PA has on health outcomes and the effectiveness of treatment interventions to increase PA. The purpose of this study was to investigate the psychometric properties of a novel computer-animated self-report questionnaire designed to assess walking activity of older adults: the Mobility Assessment Tool for Walking—the MAT-W.
We recruited 249 older adults (66.9±4.7 years, 71% female, 32% black) with cardiovascular disease and/or metabolic syndrome as part of the Cooperative Lifestyle Intervention Program-II study. Participants completed the MAT-W at baseline and after 6 months of a walking and weight loss (n = 78) or weight loss only (n = 69) intervention. Test–retest reliability was assessed in 31 participants. Walking speed at usual and fast pace was measured using a GAITRite mat, and 7-day accelerometry data were collected at baseline and 6 months. The mCHAMPS5, a modified version of a widely used self-report PA questionnaire, was completed at baseline.
The test–retest reliability of MAT-W was excellent (intraclass correlation coefficient > .85). The MAT-W was correlated with mCHAMPS5 (Spearman r = .66, p < .001) and moderate/vigorous levels of PA as assessed by accelerometry (Spearman r = .65, p < .001) and was responsive to an intervention-induced change in PA at 6 months when comparing the Cooperative Lifestyle Intervention Program-II walking and weight loss group with the weight loss only group (p < .001).
The MAT-W is a brief, reliable, and valid tool to assess PA and has promise for the assessment of walking behavior in older adults under free-living conditions.
PMCID: PMC4692966  PMID: 26261044
Physical activity assessment; Self-report measure; Exercise; Mobility
8.  Tequila Regulates Insulin-Like Signaling and Extends Life Span in Drosophila melanogaster  
The aging process is a universal phenomenon shared by all living organisms. The identification of longevity genes is important in that the study of these genes is likely to yield significant insights into human senescence. In this study, we have identified Tequila as a novel candidate gene involved in the regulation of longevity in Drosophila melanogaster. We have found that a hypomorphic mutation of Tequila (Teq f01792), as well as cell-specific downregulation of Tequila in insulin-producing neurons of the fly, significantly extends life span. Tequila deficiency–induced life-span extension is likely to be associated with reduced insulin-like signaling, because Tequila mutant flies display several common phenotypes of insulin dysregulation, including reduced circulating Drosophila insulin-like peptide 2 (Dilp2), reduced Akt phosphorylation, reduced body size, and altered glucose homeostasis. These observations suggest that Tequila may confer life-span extension by acting as a modulator of Drosophila insulin-like signaling.
PMCID: PMC4675830  PMID: 26265729
Aging; Longevity; Neurotrypsin; Glucose homeostasis
9.  Association of Urinary 6-Sulfatoxymelatonin (aMT6s) Levels and Objective and Subjective Sleep Measures in Older Men: The MrOS Sleep Study 
Sleep and melatonin have been associated with healthy aging. In this study, we examine the association between melatonin levels and sleep among older men.
Cross-sectional study of a community-dwelling cohort of 2,821 men aged 65 years or older recruited from six U.S. centers. First morning void urine samples were collected to measure melatonin’s major urinary metabolite, 6-sulfatoxymelatonin (aMT6s). We also assessed objective and subjective sleep parameters. We used logistic regression models to calculate multivariate (MV) odds ratios (ORs), and 95% confidence intervals (CIs) adjusted for important demographic variables and comorbidities.
In the overall sample, the only significant finding in fully adjusted models was that aMT6s levels were inversely associated with subjectively measured daytime sleepiness (sleepiness mean score of 5.79 in the top aMT6s quartile, and 6.26 in the bottom aMT6s quartile, MV OR, 1.32; 95% CI, 0.95–1.84; p trend ≤ .02). When restricting to men without β-blocker use (a known melatonin suppressant), aMT6s levels were significantly associated with shorter sleep time, that is, less than 5 hours (MV OR, = 1.90; 95% CI, 1.21–2.99; p trend = .01), and worse sleep efficiency, that is, less than 70% (MV OR, 1.58; 95% CI, 1.28–2.65; p trend < .001). aMT6s were not associated with subjective sleep quality or respiratory disturbance in any of our analyses.
Lower nocturnal melatonin levels were associated with worsened daytime sleepiness, sleep efficiency, and shorter sleep time in older men. The role of circadian interventions, and whether melatonin levels are a modifiable risk factor for poor sleep in older men, warrants further study.
PMCID: PMC4723659  PMID: 26265731
6-Sulfatoxymelatonin; Actigraphy; Sleepiness; Total sleep time; Sleep efficiency; Older men
10.  Shorter Ends, Faster End? Leukocyte Telomere Length and Mortality Among Older Taiwanese 
Recent studies have found mixed results regarding the association between leukocyte telomere length (LTL)—thought to be a marker of cellular aging—and all-cause mortality. Some studies have reported a significant inverse relationship, but others have not, perhaps in part owing to insufficient power. We examine the relationship using data from a nationally representative sample of older Taiwanese (54+ in 2000), which is larger (n = 942) than most previous studies, and which includes comprehensive information on potential confounders including white blood cell distribution and inflammatory markers. Results from a Cox hazards model demonstrate a small, but significant, association between LTL and mortality that is independent of age, sex, and lifestyle factors. White blood cell distribution, especially the proportion of neutrophils, is an important predictor of LTL; however, the association between LTL and mortality changes little controlling for white blood cell distribution. In contrast, the association between LTL and mortality weakens considerably (by 48%) after adjustment for inflammatory markers and homocysteine. Our results suggest that the relationship between short telomeres and mortality is tied to inflammation and homocysteine. Longitudinal studies are needed to explore bidirectional influences resulting from the fact that inflammation leads to shorter leukocyte telomeres, which in turn results in senescence, which exacerbates inflammation.
PMCID: PMC4751225  PMID: 25326284
Mortality; Telomeres; Biological aging; Taiwan; Inflammation
11.  Regulatory T Cells, Frailty, and Immune Activation in Men Who Have Sex With Men in the Multicenter AIDS Cohort Study 
Both HIV infection and frailty have been associated with chronic immune activation. One possible explanation for this chronic immune activation could be low levels of CD4+ T regulatory cells (Tregs), which suppress immune responses.
HIV-uninfected (HIV−) and HIV-infected (HIV+) men in the Multicenter AIDS Cohort Study (MACS) were classified as frail (or nonfrail) if they expressed (or did not express) the Fried frailty phenotype at two consecutive study visits. Percentages and absolute numbers of total Tregs, and percentages of different subsets of Tregs and of activated T cells were measured by flow cytometry. The function of Tregs was measured by suppression of T-cell proliferation.
Percentages of Tregs were higher, rather than lower, in frail men than in nonfrail men, and this difference was significant for HIV− men. Percentages of subsets of Tregs did not differ significantly by frailty status. Among HIV+ men, the suppressive function of Tregs was similar between frail and nonfrail men. Percentages of Tregs and activated T cells were negatively correlated in nonfrail men (HIV− and HIV+) and in frail HIV− men, but this correlation was strongly positive in frail HIV+ men.
These data suggest that: (a) Tregs were not deficient in frail men; and (b) the immunological pathophysiology of frailty may differ by HIV status.
PMCID: PMC4751226  PMID: 26297938
Frailty; Immune function; Infection; HIV/AIDS; T cells
12.  Skeletal Muscle Mitochondrial Function and Fatigability in Older Adults 
Fatigability increases while the capacity for mitochondrial energy production tends to decrease significantly with age. Thus, diminished mitochondrial function may contribute to higher levels of fatigability in older adults.
The relationship between fatigability and skeletal muscle mitochondrial function was examined in 30 participants aged 78.5 ± 5.0 years (47% female, 93% white), with a body mass index of 25.9 ± 2.7 kg/m2 and usual gait-speed of 1.2 ± 0.2 m/s. Fatigability was defined using rating of perceived exertion (6–20 point Borg scale) after a 5-minute treadmill walk at 0.72 m/s. Phosphocreatine recovery in the quadriceps was measured using 31P magnetic resonance spectroscopy and images of the quadriceps were captured to calculate quadriceps volume. ATPmax (mM ATP/s) and oxidative capacity of the quadriceps (ATPmax·Quadriceps volume) were calculated. Peak aerobic capacity (VO2peak) was measured using a modified Balke protocol.
ATPmax·Quadriceps volume was associated with VO2peak and was 162.61mM ATP·mL/s lower (p = .03) in those with high (rating of perceived exertion ≥10) versus low (rating of perceived exertion ≤9) fatigability. Participants with high fatigability required a significantly higher proportion of VO2peak to walk at 0.72 m/s compared with those with low fatigability (58.7 ± 19.4% vs 44.9 ± 13.2%, p < .05). After adjustment for age and sex, higher ATPmax was associated with lower odds of having high fatigability (odds ratio: 0.34, 95% CI: 0.11–1.01, p = .05).
Lower capacity for oxidative phosphorylation in the quadriceps, perhaps by contributing to lower VO2peak, is associated with higher fatigability in older adults.
PMCID: PMC4612379  PMID: 25167867
Mitochondrial function; Fatigability; Aerobic capacity; Skeletal muscle.
13.  Mitochondrial DNA Sequence Variation Associated With Peripheral Nerve Function in the Elderly 
Mitochondrial dysfunction is a prominent hallmark of many sensory neuropathies. The purpose of this study was to assess the influence of mitochondrial DNA sequence variation on peripheral nerve function in the population-based Health, Aging, and Body Composition Study.
We investigated the role of common mitochondrial DNA variation (n = 1,580) and complete mitochondrial DNA sequences (n = 138) on peroneal motor nerve conduction velocity and amplitude, average vibration detection threshold, and monofilament sensitivity.
Nominal associations among common mitochondrial DNA variants and haplogroups were identified but were not statistically significant after adjustment for multiple comparisons. Sequence-based approaches were used to identify aggregate variant associations across the 16S rRNA (weighted-sum, p = 2E-05 and variable threshold, p = 9E-06) for nerve conduction velocity. Several of these rare 16S variants occurred at or near sites with earlier disease associations and are also in close proximity to the peptidyl transferase center, which is the catalytic center of the 16S rRNA
These results suggest that sequence variation related to mitochondrial protein synthesis/assembly is associated with peripheral nerve function and may provide insight into targets for intervention or new clinical strategies to preserve nerve function in late life.
PMCID: PMC4612380  PMID: 25394619
Sensory; Genetics; Epidemiology; Functional Performance.
14.  Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging 
Adipose tissue inflammation has been linked to age-related metabolic diseases. However, the underlying mechanisms are poorly understood. Adipose tissue inflammation and insulin resistance in diet associated obesity has been correlated with aberrant endoplasmic reticulum (ER) stress. This study was undertaken to test our hypothesis that increased ER stress response contributes to age-associated adipose tissue inflammation. We found elevated ER stress response in adipose tissue of old (18–20 months) compared to young (4–6 months) mice. Elevated ER stress markers BIP (GRP78), CHOP, cleaved-ATF-6, phospho-IRE1α, and XBP-1 were observed in old compared to young adipose tissue stromal cells. Additionally, old adipose tissue stromal cells were more sensitive to an ER stress inducer, thapsigargin. Similar experiments with adipose tissue macrophages showed elevated Chop and Bip expression in old adipose tissue macrophages when induced with thapsigargin. Treatment of chemical chaperone 4-phenyle-butyric acid alleviated ER stress in adipose tissue stromal cells and adipose tissue macrophages and attenuated the production of IL-6 and MCP-1 by adipose tissue stromal cells, and TNF-α by adipose tissue macrophages from both young and old mice. Finally, old mice fed with 4-phenyle-butyric acid have reduced expression of ER stress and inflammatory cytokine genes. Our data suggests that an exaggerated ER stress response in aging adipose tissue contributes to age-associated inflammation that can be mitigated by treatment with chemical chaperones.
PMCID: PMC4612381  PMID: 25324219
Aging; Adipose tissue; ER stress response; Chemical chaperones.
15.  Use of Nerve Conduction Velocity to Assess Peripheral Nerve Health in Aging Mice 
Nerve conduction velocity (NCV), the speed at which electrical signals propagate along peripheral nerves, is used in the clinic to evaluate nerve function in humans. A decline in peripheral nerve function is associated with a number of age-related pathologies. While several studies have shown that NCV declines with age in humans, there is little information on the effect of age on NCV in peripheral nerves in mice. In this study, we evaluated NCV in male and female C57Bl/6 mice ranging from 4 to 32 months of age. We observed a decline in NCV in both male and female mice after 20 months of age. Sex differences were detected in sensory NCV as well as the rate of decline during aging in motor nerves; female mice had slower sensory NCV and a slower age-related decline in motor nerves compared with male mice. We also tested the effect of dietary restriction on NCV in 30-month-old female mice. Dietary restriction prevented the age-related decline in sciatic NCV but not other nerves. Because NCV is clinically relevant to the assessment of nerve function, we recommend that NCV be used to evaluate healthspan in assessing genetic and pharmacological interventions that increase the life span of mice.
PMCID: PMC4612382  PMID: 25477428
Peripheral nerves; Dietary restriction; Nerve conduction.
16.  Energy Metabolism and the Burden of Multimorbidity in Older Adults: Results From the Baltimore Longitudinal Study of Aging 
Excessively elevated resting metabolic rate (RMR) for persons of a certain age, sex, and body composition is a mortality risk factor. Whether elevated RMR constitutes an early marker of health deterioration in older adult has not been fully investigated. Using data from the Baltimore Longitudinal Study of Aging, we hypothesized that higher RMR (i) was cross-sectionally associated with higher multimorbidity and (ii) predicted higher multimorbidity in subsequent follow-ups. The analysis included 695 Baltimore Longitudinal Study of Aging participants, aged 60 or older at baseline, of whom 248 had follow-up data available 2 years later and 109 four years later. Multimorbidity was assessed as number of chronic diseases. RMR was measured by indirect calorimetry and was tested in regression analyses adjusted for covariates age, sex, and dual-energy x-ray absorptiometry–measured total body fat mass and lean mass. Baseline RMR and multimorbidity were positively associated, independent of covariates (p = .002). Moreover, in a three-wave bivariate autoregressive cross-lagged model adjusted for covariates, higher prior RMR predicted greater future multimorbidity above and beyond the cross-sectional and autoregressive associations (p = .034). RMR higher than expected, given age, sex, and body composition, predicts future higher multimorbidity in older adults and may be used as early biomarker of impending health deterioration. Replication and the development of normative data are required for clinical translation.
PMCID: PMC4612383  PMID: 25409892
Multimorbidity; Resting metabolic rate; Aging; Health status; Metabolism.
17.  Differential Effect of Endurance Training on Mitochondrial Protein Damage, Degradation, and Acetylation in the Context of Aging 
Acute aerobic exercise increases reactive oxygen species and could potentially damage proteins, but exercise training (ET) enhances mitochondrial respiration irrespective of age. Here, we report a differential impact of ET on protein quality in young and older participants. Using mass spectrometry we measured oxidative damage to skeletal muscle proteins before and after 8 weeks of ET and find that young but not older participants reduced oxidative damage to both total skeletal muscle and mitochondrial proteins. Young participants showed higher total and mitochondrial derived semitryptic peptides and 26S proteasome activity indicating increased protein degradation. ET however, increased the activity of the endogenous antioxidants in older participants. ET also increased skeletal muscle content of the mitochondrial deacetylase SIRT3 in both groups. A reduction in the acetylation of isocitrate dehydrogenase 2 was observed following ET that may counteract the effect of acute oxidative stress. In conclusion aging is associated with an inability to improve skeletal muscle and mitochondrial protein quality in response to ET by increasing degradation of damaged proteins. ET does however increase muscle and mitochondrial antioxidant capacity in older individuals, which provides increased buffering from the acute oxidative effects of exercise.
PMCID: PMC4612384  PMID: 25504576
Mitochondria; Sarcopenia; Aging; Oxidative damage; Proteasome.
18.  Aging Exacerbates Pressure-Induced Mitochondrial Oxidative Stress in Mouse Cerebral Arteries 
Epidemiological studies demonstrate that in addition to the increased prevalence of hypertension in old patients, the deleterious cerebrovascular effects of hypertension (including atherosclerosis, stroke, and vascular cognitive impairment) are also exacerbated in elderly individuals. The cellular mechanisms by which aging and hypertension interact to promote cerebrovascular pathologies are not well understood. To test the hypothesis that aging exacerbates high pressure–induced mitochondrial oxidative stress, we exposed isolated segments of the middle cerebral arteries of young (3 months) and aged (24 months) C57BL/6 mice to 60 or 140 mmHg intraluminal pressure and assessed changes in mitochondrial reactive oxygen species production using a mitochondria-targeted redox-sensitive fluorescent indicator dye (MitoSox) by confocal microscopy. Perinuclear MitoSox fluorescence was significantly stronger in high pressure–exposed middle cerebral arteries compared with middle cerebral arteries of the same animals exposed to 60 mmHg, indicating that high pressure increases mitochondrial reactive oxygen species production in the smooth muscle cells of cerebral arteries. Comparison of young and aged middle cerebral arteries showed that aging exacerbates high pressure–induced mitochondrial reactive oxygen species production in cerebral arteries. We propose that increased mechanosensitive mitochondrial oxidative stress may potentially exacerbate cerebrovascular injury and vascular inflammation in aging.
PMCID: PMC4612385  PMID: 25631392
Hypertension; Middle cerebral artery; Oxidative stress; Mitochondrion; Free radicals.
19.  Dietary Fatty Acids and Temperature Modulate Mitochondrial Function and Longevity in Drosophila  
Fluctuations in temperature and resource availability are conditions many organisms contend with in nature. Specific dietary nutrients such as fatty acids play an essential role in reproduction, cold adaptation, and metabolism in a variety of organisms. The present study characterizes how temperature and diet interact to modulate Drosophila physiology and life span. Flies were raised on media containing specific saturated, monounsaturated, or polyunsaturated fatty acids supplements at low concentrations and were placed in varied thermal environments. We found that dietary long-chain polyunsaturated fatty acids improve chill coma recovery and modulate mitochondrial function. Additionally, monounsaturated and polyunsaturated fatty acid food supplements were detrimental to life span regardless of temperature, and antioxidants were able to partially rescue this effect. This study provides insight into environmental modulation of Drosophila physiology and life span.
PMCID: PMC4612386  PMID: 25910846
Temperature; Diet; Fatty acids; Drosophila; Antioxidant; Longevity.
20.  Reconsidering the Role of Mitochondria in Aging 
Background: Mitochondrial dysfunction has long been considered a major contributor to aging and age-related diseases. Harman’s Mitochondrial Free Radical Theory of Aging postulated that somatic mitochondrial DNA mutations that accumulate over the life span cause excessive production of reactive oxygen species that damage macromolecules and impair cell and tissue function. Indeed, studies have shown that maximal oxidative capacity declines with age while reactive oxygen species production increases. Harman’s hypothesis has been seriously challenged by recent studies showing that reactive oxygen species evoke metabolic health and longevity, perhaps through hormetic mechanisms that include autophagy. The purpose of this review is to scan the ever-growing literature on mitochondria from the perspective of aging research and try to identify priority questions that should be addressed in future research.Methods: A systematic search of peer-reviewed studies was performed using PubMed. Search terms included (i) mitochondria or mitochondrial; (ii) aging, ageing, older adults or elderly; and (iii) reactive oxygen species, mitochondria dynamics, mitochondrial proteostasis, cytosol, mitochondrial-associated membranes, redox homeostasis, electron transport chain, electron transport chain efficiency, epigenetic regulation, DNA heteroplasmy.Results: The importance of mitochondrial biology as a trait d’union between the basic biology of aging and the pathogenesis of age-related diseases is stronger than ever, although the emphasis has moved from reactive oxygen species production to other aspects of mitochondrial physiology, including mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics. Conclusions: Mitochondria could play a key role in the pathophysiology of aging or in the earlier stages of some events that lead to the aging phenotype. Therefore, mitochondria will increasingly be targeted to prevent and treat chronic diseases and to promote healthy aging.
PMCID: PMC4612387  PMID: 25995290
Mitochondria; Aging; Lifespan
21.  Mitochondrial DNA Heteroplasmy Associations With Neurosensory and Mobility Function in Elderly Adults 
Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at specific mtDNA sites lead to inherited mitochondrial diseases with neurological, sensory, and movement impairments. Here we test the hypothesis that heteroplasmy levels in elderly adults are associated with impaired function resembling mild forms of mitochondrial disease.
We examined platelet mtDNA heteroplasmy at 20 disease-causing sites for associations with neurosensory and mobility function among 137 participants from the community-based Health, Aging, and Body Composition Study.
Elevated mtDNA heteroplasmy at four mtDNA sites in complex I and tRNA genes was nominally associated with reduced cognition, vision, hearing, and mobility: m.10158T>C with Modified Mini-Mental State Examination score (p = .009); m.11778G>A with contrast sensitivity (p = .02); m.7445A>G with high-frequency hearing (p = .047); and m.5703G>A with 400 m walking speed (p = .007).
These results indicate that increased mtDNA heteroplasmy at disease-causing sites is associated with neurosensory and mobility function in older persons. We propose the novel use of mtDNA heteroplasmy as a simple, noninvasive predictor of age-related neurologic, sensory, and movement impairments.
PMCID: PMC4612388  PMID: 26328603
Mitochondrial DNA; Heteroplasmy; Cognition; Vision; Hearing; Mobility.
22.  Medicare Utilization and Expenditures Around Incident Dementia in a Multiethnic Cohort 
Few studies have examined patterns of health care utilization and costs during the period around incident dementia.
Participants were drawn from the Washington Heights-Inwood Columbia Aging Project, a multiethnic, population-based, prospective study of cognitive aging of Medicare beneficiaries in a geographically defined area of northern Manhattan. Medicare utilization and expenditure were examined in individuals with clinically diagnosed dementia from 2 years before until 2 years after the initial diagnosis. A sample of non-demented individuals who were matched on socio-demographic and clinical characteristics at study enrollment was used as controls. Multivariable regression analysis estimated effects on Medicare utilization and expenditures associated with incident dementia.
During the 2 years before incident dementia, rates of inpatient admissions and outpatient visits were similar between dementia patients and non-demented controls, but use of home health and skilled nursing care and durable medical equipment were already higher in dementia patients. Results showed a small but significant excess increase associated with incident dementia in inpatient admissions but not in other areas of care. In the 2 years before incident dementia, total Medicare expenditures were already higher in dementia patients than in non-demented controls. But we found no excess increases in Medicare expenditures associated with incident dementia.
Demand for medical care already is increasing and costs are higher at the time of incident dementia. There was a small but significant excess risk of inpatient admission associated with incident dementia.
PMCID: PMC4612389  PMID: 26311543
Incident dementia; Medicare; Health care use; Health care expenditures; Longitudinal follow-up
23.  Mitochondrial Aging and Physical Decline: Insights From Three Generations of Women 
Decline in mitochondrial DNA (mtDNA) copy number, function, and accumulation of mutations and deletions have been proposed to contribute to age-related physical decline, based on cross sectional studies in genetically unrelated individuals. There is wide variability of mtDNA and functional measurements in many population studies and therefore we assessed mitochondrial function and physical function in 18 families of grandmothers, mothers, and daughters who share the same maternally inherited mtDNA sequence. A significant age-related decline in mtDNA copy number, mitochondrial protein expression, citrate synthase activity, cytochrome c oxidase content, and VO2 peak were observed. Also, a lower abundance of SIRT3, accompanied by an increase in acetylated skeletal muscle proteins, was observed in grandmothers. Muscle tissue–based full sequencing of mtDNA showed greater than 5% change in minor allele frequency over a lifetime in two locations, position 189 and 408 in the noncoding D-loop region but no changes were noted in blood cells mtDNA. The decline in oxidative capacity and muscle function with age in three generations of women who share the same mtDNA sequence are associated with a decline in muscle mtDNA copy number and reduced protein deacetylase activity of SIRT3.
PMCID: PMC4675931  PMID: 26297939
Mitochondrial DNA; Aging; SIRT3; Oxidative capacity; Acetylated protein; Skeletal muscle
24.  Recovery of Indicators of Mitochondrial Biogenesis, Oxidative Stress, and Aging With (−)-Epicatechin in Senile Mice 
There is evidence implicating oxidative stress (OS) as the cause of the deleterious effects of aging. In this study, we evaluated the capacity of the flavanol (−)-epicatechin (Epi) to reduce aging-induced OS and restore mitochondrial biogenesis, as well as, structural and functional endpoints in aged mice. Senile (S; 26-month-old) C57BL/6 male mice were randomly assigned to receive either water (vehicle) or 1mg/kg of Epi via oral gavage (twice daily) for 15 days. Young (Y; 6-month-old) mice were used as controls. In S brain, kidney, heart, and skeletal muscle (compared with Y animals) an increase in OS was observed as evidenced by increased protein-free carbonyls and decreased reduced glutathione levels as well as sirtuin 3, superoxide dismutase 2, catalase, thioredoxin and glutathione peroxidase protein levels. Well-recognized factors (eg, sirtuin 1) that regulate mitochondrial biogenesis and mitochondrial structure- and/or function-related endpoints (eg, mitofilin and citrate synthase) protein levels were also reduced in S organs. In contrast, the aging biomarker senescence-associated β-galactosidase was increased in S compared with Y animals, and Epi administration reduced levels towards those observed in Y animals. Altogether, these data suggest that Epi is capable of shifting the biology of S mice towards that of Y animals.
PMCID: PMC4715241  PMID: 25143004
(−)-Epicatechin; Oxidative stress; Mitochondrial biogenesis; Senescence-associated β-galactosidase.
25.  The Rate of Age-Related Olfactory Decline Among the General Population of Older U.S. Adults 
Age-related olfactory loss (presbyosmia) is a prevalent sensory impairment with a large public health impact. In cross-sectional analyses, we found striking health disparities in olfactory function among older U.S. adults. Here, we report a 5-year follow-up to determine the magnitude of within-person olfactory decline.
The National Social Life, Health, and Aging Project (NSHAP) interviewed a probability sample of home-dwelling older U.S. adults (57–85 years) in 2005–2006 (Wave 1) and reinterviewed them in 2010–2011 (Wave 2), assessing demographics, social life, and health, including olfaction. Odor identification was measured with a 5-item version of the Sniffin’ Sticks (0–5 correct). Fourteen hundred and thirty-six respondents provided olfaction data in both waves. Multivariate linear and logistic regression were used to model the association between change in olfactory performance and demographic, health, and psychosocial factors.
Odor identification declined most rapidly among older individuals (0.25 additional errors per 5 years for each decade of age, p < .001) and in men (0.17 additional errors per 5 years compared to women, p = .005). Among those with perfect scores in Wave 1, African Americans declined more rapidly than Whites (p = .04). Neither socioeconomic status, health conditions, cognition, mental health, alcohol use nor smoking was associated with change in olfaction (p > .05, all).
The rate of olfactory decline increases with age and is greater among men than women despite adjusting for differences in psychosocial and health conditions, indicating physiologic factors as drivers. African Americans are more likely to experience initial olfactory decline, consistent with an earlier onset of aging among this subgroup.
PMCID: PMC4715242  PMID: 26253908
Epidemiology; Health disparities; Minority aging; Sensory; Neurological.

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