Publications by authors named "Luigi Ferrucci"

1,334 Publications

  • Page 1 of 1

The Plasma Proteome Fingerprint Associated With Circulating Carotenoids And Retinol In Older Adults.

J Nutr 2021 Sep 22. Epub 2021 Sep 22.

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Although diets rich in carotenoids are associated with reduced risk of cardiovascular disease, age-related macular degeneration, disability, and other adverse aging outcomes, the underlying biological mechanisms are not fully elucidated.

Objectives: To characterize the plasma proteome fingerprint associated with circulating carotenoid and retinol concentrations in older adults.

Methods: In 728 adults, ≥65 years, participating in the Invecchiare in Chianti (InCHIANTI) Study, plasma α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene were measured using high performance liquid chromatography. The SOMAscan assay was used to measure 1301 plasma proteins. Multivariable linear regression models were used to examine the relationship of individual carotenoids and retinol with plasma proteins. A false discovery rate approach was used to deal with multiple comparisons using a q-value <0.05.

Results: Plasma β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene were associated with 85, 39, 4, 2, and 5 plasma proteins, respectively, in multivariable linear regression models adjusting for potential confounders (q<0.05). No proteins were associated with α-carotene or retinol. Two or more carotenoids were positively associated with ferritin, 6-phosphogluconate dehydrogenase (decarboxylating), hepcidin, thrombospondin-2, and choline/ethanolamine kinase. The proteins associated with circulating carotenoids were related to energy metabolism, sirtuin signaling, inflammation and oxidative stress, iron metabolism, proteostasis, innate immunity, and longevity.

Conclusions: The plasma proteomic fingerprint associated with elevated circulating carotenoids in older adults provide insight into the mechanisms underlying the protective role of carotenoids on health.
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http://dx.doi.org/10.1093/jn/nxab340DOI Listing
September 2021

Investigating RFC1 expansions in sporadic amyotrophic lateral sclerosis.

J Neurol Sci 2021 Aug 31;430:118061. Epub 2021 Aug 31.

Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Neurology Department, Johns Hopkins University, Baltimore, MD 21205, USA.

A homozygous AAGGG repeat expansion within the RFC1 gene was recently described as a common cause of CANVAS syndrome. We examined 1069 sporadic ALS patients for the presence of this repeat expansion. We did not discover any carriers of the homozygous AAGGG expansion in our ALS cohort, indicating that this form of RFC1 repeat expansions is not a common cause of sporadic ALS. However, our study did identify a novel repeat conformation and further expanded on the highly polymorphic nature of the RFC1 locus.
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http://dx.doi.org/10.1016/j.jns.2021.118061DOI Listing
August 2021

Longitudinal associations of subclinical hearing loss with cognitive decline.

J Gerontol A Biol Sci Med Sci 2021 Sep 13. Epub 2021 Sep 13.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA.

Background: Several studies have demonstrated that age-related hearing loss is associated with cognitive decline. We investigated whether subclinical hearing loss (SCHL), or imperfect hearing traditionally categorized as normal (pure tone average ≤25 dB), may be similarly linked to cognitive decline and risk of incident mild cognitive impairment (MCI)/dementia.

Methods: Participants from the Baltimore Longitudinal Study of Aging were cognitively normal adults ≥50 years old with cognitive assessments from 1991-2019 and pure-tone average ≤25 dB measured between 1991-1994 (n=263). The exposure was hearing based on the better ear pure-tone average. Outcomes were test scores in various cognitive domains. Multivariable linear-mixed effects models modeled the association between hearing and change in cognition over time, adjusting for age, sex, education, vascular burden, and race. Kaplan-Meier survival curves and Cox proportional hazards models portrayed associations between hearing and incident MCI/dementia diagnosis based on predefined criteria.

Results: Of 263 participants, 145 (55.1%) were female; mean age was 68.3 years (standard deviation, SD=8.9). Follow-up ranged up to 27.7 years (mean=11.7 years). Adjusting for multiple comparisons, a 10-dB increase in hearing loss was associated with an annual decline of -0.02 SDs (95% confidence interval, [CI]: -0.03, -0.01) in Letter Fluency. No significant relationships were observed between hearing and incident MCI/dementia.

Conclusions: A relationship between SCHL and cognitive decline was observed for the Letter Fluency test. Further studies are necessary to determine when in the spectrum of hearing loss there begins to be an observable relationship between hearing and cognitive decline.
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http://dx.doi.org/10.1093/gerona/glab263DOI Listing
September 2021

Fasting blood glucose as a predictor of mortality: Lost in translation.

Cell Metab 2021 Sep 8. Epub 2021 Sep 8.

Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA. Electronic address:

Aging leads to profound changes in glucose homeostasis, weight, and adiposity, which are considered good predictors of health and survival in humans. Direct evidence that these age-associated metabolic alterations are recapitulated in animal models is lacking, impeding progress to develop and test interventions that delay the onset of metabolic dysfunction and promote healthy aging and longevity. We compared longitudinal trajectories, rates of change, and mortality risks of fasting blood glucose, body weight, and fat mass in mice, nonhuman primates, and humans throughout their lifespans and found similar trajectories of body weight and fat in the three species. In contrast, fasting blood glucose decreased late in life in mice but increased over the lifespan of nonhuman primates and humans. Higher glucose was associated with lower mortality in mice but higher mortality in nonhuman primates and humans, providing a cautionary tale for translating age-associated metabolic changes from mice to humans.
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http://dx.doi.org/10.1016/j.cmet.2021.08.013DOI Listing
September 2021

Combined evaluation of aminotransferases improves risk stratification for overall and cause-specific mortality in older patients.

Aging Clin Exp Res 2021 Sep 10. Epub 2021 Sep 10.

Clinical Medicine and Hepatology Unit, Campus Bio-Medico University, Rome, Italy.

Background: Recent studies identified low levels of alanine aminotransferase (ALT) as strong predictors of mortality in older people.

Aims: Here we verified if the combined evaluation of aminotransferases may improve risk stratification for adverse outcomes in older patients.

Methods: Data are from 761 participants aged more than 65 years from a prospective population-based database (InCHIANTI study), without known baseline chronic liver disease or malignancies. Associations between aminotransferase levels and the risk of all-cause, cardiovascular- and cancer-death were assessed by Cox-models with time-dependent covariates.

Results: The association of ALT and aspartate aminotransferase (AST) with mortality was non-linear, mirroring a J- and a U-shaped curve, respectively. Based on quintiles of transaminase activities and on their association with overall mortality, low, intermediate (reference group) and high levels were defined. Having at least one transaminase in the low range [aHR 1.76 (1.31-2.36), p < 0.001], mainly if both [(aHR 2.39 (1.81-3.15), p < 0.001], increased the risk of overall mortality, as well as having both enzymes in the high range [aHR 2.14 (1.46-3.15), p < 0.001]. While similar trends were confirmed with respect to cardiovascular mortality, subjects with the highest risk of cancer mortality were those with both enzymes in the high range [aHR 3.48 (1.43-8.44), p = 0.006]. Low levels of transaminases were associated with frailty, sarcopenia and disability, while high levels did not capture any known proxy of adverse outcome. Conclusions and discussion The prognostic information is maximized by the combination of the 2 liver enzymes. While both aminotransferases in low range are characteristically found in the most fragile phenotype, both enzymes in high range are more likely to identify new-onset vascular/infiltrative diseases with adverse outcome.
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http://dx.doi.org/10.1007/s40520-021-01979-9DOI Listing
September 2021

Extending human healthspan and longevity: a symposium report.

Ann N Y Acad Sci 2021 Sep 8. Epub 2021 Sep 8.

The Buck Institute for Research on Aging, Novato, California.

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.
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http://dx.doi.org/10.1111/nyas.14681DOI Listing
September 2021

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

JAMA Intern Med 2021 Sep 7. Epub 2021 Sep 7.

Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.

Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.

Design, Setting, And Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.

Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.

Main Outcomes And Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.

Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.

Conclusions And Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
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http://dx.doi.org/10.1001/jamainternmed.2021.5078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424529PMC
September 2021

Association of walking energetics with amyloid beta status: Findings from the Baltimore Longitudinal Study of Aging.

Alzheimers Dement (Amst) 2021 20;13(1):e12228. Epub 2021 Aug 20.

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland USA.

Introduction: Higher energetic costs for mobility predict gait speed decline. Slow gait is linked to cognitive decline and Alzheimer's disease (AD). Whether the energetic cost of walking is linked to AD pathology is unknown. We investigated the cross-sectional association between the energetic cost of walking, gait speed, and amyloid beta (Aβ) status (+/-) in older adults.

Methods: One hundred forty-nine cognitively normal adults (56% women, mean age 77.5 ± 8.4 years) completed customary-paced walking assessments with indirect calorimetry and C-Pittsburgh compound B positron emission tomography. Logistic regression models examined associations adjusted for demographics, body composition, comorbid conditions, and apolipoprotein E ε4.

Results: Each 0.01 mL/kg/m greater energy cost was associated with 18% higher odds of being Aβ+ (odds ratio [OR] = 1.18; 95% confidence interval [CI]: 1.04 to 1.34; = .011). These findings were not observed when investigating gait speed (OR = 0.99; 95% CI: 0.97 to 1.01; = .321).

Discussion: High energetic cost of walking is linked to AD pathology and may be a potential target for therapeutic intervention.
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http://dx.doi.org/10.1002/dad2.12228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377776PMC
August 2021

Association of Physical Activity With Maximal and Submaximal Tests of Exercise Capacity in Middle- and Older-Aged Adults.

J Aging Phys Act 2021 Aug 18:1-10. Epub 2021 Aug 18.

Although physical activity (PA) is an important determinant of exercise capacity, the association between these constructs is modest. The authors investigated the associations of self-reported and objectively measured PA with maximal and submaximal tests of exercise capacity. Participants aged ≥40 years (N = 413; 49.6% female) completed a PA questionnaire, wore a uniaxial accelerometer (5.2 ± 1.1 days), and performed maximal (cardiopulmonary exercise test [CPET]) and submaximal (long-distance corridor walk) tests with indirect calorimetry (oxygen consumption, V˙O2). Linear regression models were fitted to assess the variation in exercise capacity explained (partial eta squared, η2) by PA variables. Accelerometer-measured vigorous (η2 = 22% female; η2 = 16% male) and total PA (η2 = 17% female; η2 = 13% male) explained the most variance in CPET V˙O2 (p < .001). All η2 values were lower for long-distance corridor walk V˙O2 (η2 ≤ 11%). Age contributed more to CPET V˙O2 than any PA variable in males (η2 = 32%), but not in females (η2 = 19%). Vigorous and total PA play important roles in CPET V˙O2 in mid to late life.
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http://dx.doi.org/10.1123/japa.2020-0439DOI Listing
August 2021

Empirical versus theoretical power and type I error (false-positive) rates estimated from real murine aging research data.

Cell Rep 2021 Aug;36(7):109560

Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address:

We assess the degree of phenotypic variation in a cohort of 24-month-old male C57BL/6 mice. Because murine studies often use small sample sizes, if the commonly relied upon assumption of a normal distribution of residuals is not met, it may inflate type I error rates. In this study, 3-20 mice are resampled from the empirical distributions of 376 mice to create plasmodes, an approach for computing type I error rates and power for commonly used statistical tests without assuming a normal distribution of residuals. While all of the phenotypic and metabolic variables studied show considerable variability, the number of animals required to achieve adequate power is markedly different depending on the statistical test being performed. Overall, this work provides an analysis with which researchers can make informed decisions about the sample size required to achieve statistical power from specific measurements without a priori assumptions of a theoretical distribution.
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http://dx.doi.org/10.1016/j.celrep.2021.109560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449850PMC
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Disease Burden Affects Aging Brain Function.

J Gerontol A Biol Sci Med Sci 2021 Jul 30. Epub 2021 Jul 30.

Intramural Research Program, National Institute on Aging, NIH.

Background: Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear.

Methods: We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n=74) over 5.05 (2.74 SD) years.

Results: At baseline, voxel-based analysis showed that higher multimorbidity scores were associated with lower relative activity in orbitofrontal, superior frontal, temporal pole and parahippocampal regions, and greater activity in lateral temporal, occipital and cerebellar regions. Examination of the individual health conditions comprising the index score showed hypertension and chronic kidney disease individually contributed to the overall multimorbidity pattern of altered activity. Longitudinally, both increases and decreases in activity were seen in relation to increasing multimorbidity over time. These associations were identified in orbitofrontal, lateral temporal, brainstem, and cerebellar areas.

Conclusion: Together, these results show that greater multimorbidity is associated with widespread areas of altered brain activity, supporting a link between health and changes in aging brain function.
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http://dx.doi.org/10.1093/gerona/glab218DOI Listing
July 2021

Contribution of Intramyocellular Lipids to Decreased Computed Tomography Muscle Density With Age.

Front Physiol 2021 30;12:632642. Epub 2021 Jun 30.

Laboratory of Clinical Investigation, NIA, NIH, Baltimore, MD, United States.

Skeletal muscle density, as determined by computed tomography (CT), has been shown to decline with age, resulting in increased frailty and morbidity. However, the mechanism underlying this decrease in muscle density remains elusive. We sought to investigate the role of intramyocellular lipid (IMCL) accumulation in the age-related decline in muscle density. Muscle density was measured using computerized tomography (CT), and IMCL content was quantified using proton magnetic resonance spectroscopy (H-MRS). The study population consisted of 314 healthy participants (142 men, 32-98 years) of the Baltimore Longitudinal Study of Aging (BLSA). In addition to IMCL quantification, obesity-related covariates were measured, including body mass index (BMI), waist circumference, and circulating triglyceride concentration. Higher IMCL concentrations were significantly correlated with lower muscle density in older individuals, independent of age, sex, race, and the obesity-associated covariates ( < 0.01). Lower muscle density was also significantly associated with greater age-adjusted IMCL, a variable we constructed using LOESS regression ( < 0.05). Our results suggest that the accumulation of IMCL may be associated with a decrease in muscle density. This may serve to define a potential therapeutic target for treatment of age-associated decreased muscle function.
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http://dx.doi.org/10.3389/fphys.2021.632642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279780PMC
June 2021

Association of Vision Impairment With Cognitive Decline Across Multiple Domains in Older Adults.

JAMA Netw Open 2021 Jul 1;4(7):e2117416. Epub 2021 Jul 1.

Johns Hopkins Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Associations between visual and global cognitive impairments have been previously documented, but there is limited research examining these associations between multiple measures of vision across cognitive domains.

Objective: To examine the association between vision and cognitive across multiple cognitive domains using multiple measures of vision.

Design, Setting, And Participants: This longitudinal cohort study used data from the Baltimore Longitudinal Study of Aging for 2003 to 2019. Participants in the current study were aged 60 to 94 years with vision and cognitive measures. Data analysis was performed from May 2020 to May 2021.

Main Outcomes And Measures: Cognitive function was measured across multiple domains, including language, memory, attention, executive function, and visuospatial ability. Cognitive domain scores were calculated as the mean of standardized cognitive test scores within each domain. Visual function was assessed using measures of visual acuity, contrast sensitivity, and stereo acuity at baseline.

Results: Analyses included 1202 participants (610 women [50.8%]; 853 White participants [71.0%]) with a mean (SD) age of 71.1 (8.6) years who were followed up for a mean (SD) of 6.9 (4.7) years. Worse visual acuity (per 0.1 logarithm of the minimal angle of resolution) at baseline was associated with greater declines in language (β, -0.0035; 95% CI, -0.007 to -0.001) and memory (β, -0.0052; 95% CI, -0.010 to -0.001) domain scores. Worse contrast sensitivity (per 0.1 log units) at baseline was associated with greater declines in language (β, -0.010; 95% CI, -0.014 to -0.006), memory (β, -0.009; 95% CI, -0.015 to -0.003), attention (β, -0.010; 95% CI, -0.017 to -0.003), and visuospatial ability (β, -0.010; 95% CI, -0.017 to -0.002) domain scores. Over the follow-up period, declines on tests of language (β, -0.019; 95% CI, -0.034 to -0.005) and memory (β, -0.032; 95% CI, -0.051 to -0.012) were significantly greater for participants with impaired stereo acuity compared with those without such impairment.

Conclusions And Relevance: These findings suggest that the association between vision and cognition differs between visual acuity, contrast sensitivity, and stereo acuity and that patterns of cognitive decline may differ by type of vision impairment, with impaired contrast sensitivity being associated with declines across more cognitive domains than other measures of visual functioning.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.17416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285732PMC
July 2021

Metabolomic profiles of being physically active and less sedentary: a critical review.

Metabolomics 2021 07 10;17(7):68. Epub 2021 Jul 10.

Longitudinal Studies Section, Translational Gerontology Branch, National Institute On Aging, Baltimore, MD, USA.

Background: Being physically active has multiple salutary effects on human health, likely mediated by changes in energy metabolism. Recent reviews have summarized metabolomic responses to acute exercise. However, metabolomic profiles of individuals who exercise regularly are heterogeneous.

Aim Of Review: We conducted a systematic review to identify metabolites associated with physical activity (PA), fitness, and sedentary time in community-dwelling adults and discussed involved pathways. Twenty-two studies were eligible because they (1) focused on community-dwelling adults from observational studies; (2) assessed PA, fitness, and/or sedentary time, (3) assessed metabolomics in biofluid, and (4) reported on relationships of metabolomics with PA, fitness, and/or sedentary time.

Key Scientific Concepts Of Review: Several metabolic pathways were associated with higher PA and fitness and less sedentary time, including tricarboxylic acid cycle, glycolysis, aminoacyl-tRNA biosynthesis, urea cycle, arginine biosynthesis, branch-chain amino acids, and estrogen metabolism. Lipids were strongly associated with PA. Cholesterol low-density lipoproteins and triglycerides were lower with higher PA, while cholesterol high-density lipoproteins were higher. Metabolomic profiles of being physically active and less sedentary indicate active skeletal muscle biosynthesis supported by enhanced oxidative phosphorylation and glycolysis and associated with profound changes in lipid and estrogen metabolism. Future longitudinal studies are needed to understand whether these metabolomic changes account for health benefits associated with PA.
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http://dx.doi.org/10.1007/s11306-021-01818-yDOI Listing
July 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Investigation of the association between cerebral iron content and myelin content in normative aging using quantitative magnetic resonance neuroimaging.

Neuroimage 2021 10 15;239:118267. Epub 2021 Jun 15.

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, 21224 MD, United States. Electronic address:

Myelin loss and iron accumulation are cardinal features of aging and various neurodegenerative diseases. Oligodendrocytes incorporate iron as a metabolic substrate for myelin synthesis and maintenance. An emerging hypothesis in Alzheimer's disease research suggests that myelin breakdown releases substantial stores of iron that may accumulate, leading to further myelin breakdown and neurodegeneration. We assessed associations between iron content and myelin content in critical brain regions using quantitative magnetic resonance imaging (MRI) on a cohort of cognitively unimpaired adults ranging in age from 21 to 94 years. We measured whole-brain myelin water fraction (MWF), a surrogate of myelin content, using multicomponent relaxometry, and whole-brain iron content using susceptibility weighted imaging in all individuals. MWF was negatively associated with iron content in most brain regions evaluated indicating that lower myelin content corresponds to higher iron content. Moreover, iron content was significantly higher with advanced age in most structures, with men exhibiting a trend towards higher iron content as compared to women. Finally, relationship between MWF and age, in all brain regions investigated, suggests that brain myelination continues until middle age, followed by degeneration at older ages. This work establishes a foundation for further investigations of the etiology and sequelae of myelin breakdown and iron accumulation in neurodegeneration and may lead to new imaging markers for disease progression and treatment.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370037PMC
October 2021

Proteomics and Epidemiological Models of Human Aging.

Front Physiol 2021 31;12:674013. Epub 2021 May 31.

Biomedical Research Center, National Institute on Aging, National Institute of Health, Baltimore, MD, United States.

Human aging is associated with a decline of physical and cognitive function and high susceptibility to chronic diseases, which is influenced by genetics, epigenetics, environmental, and socio-economic status. In order to identify the factors that modulate the aging process, established measures of aging mechanisms are required, that are both robust and feasible in humans. It is also necessary to connect these measures to the phenotypes of aging and their functional consequences. In this review, we focus on how this has been addressed from an epidemiologic perspective using proteomics. The key aspects of epidemiological models of aging can be incorporated into proteomics and other omics which can provide critical detailed information on the molecular and biological processes that change with age, thus unveiling underlying mechanisms that drive multiple chronic conditions and frailty, and ideally facilitating the identification of new effective approaches for prevention and treatment.
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http://dx.doi.org/10.3389/fphys.2021.674013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202502PMC
May 2021

Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease.

Circ Res 2021 Jun 10;128(12):1851-1867. Epub 2021 Jun 10.

Division of Intramural Research, National Institute on Aging (L.H., L.F.).

Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.318242DOI Listing
June 2021

Perceived Versus Objective Change in Walking Ability in Peripheral Artery Disease: Results from 3 Randomized Clinical Trials of Exercise Therapy.

J Am Heart Assoc 2021 Jun 2;10(12):e017609. Epub 2021 Jun 2.

Department of Medicine University of Chicago IL.

Background In people with lower-extremity peripheral artery disease, the effects of exercise on patient-reported outcomes remain unclear. Methods and Results Four hundred four people with peripheral artery disease in 3 clinical trials were randomized to exercise (N=205) or a control group (N=199) and completed the 6-minute walk and the Walking Impairment Questionnaire distance score (score 0-100, 100=best) at baseline and 6-month follow-up. Compared with the control group, exercise improved 6-minute walk distance by +39.8 m (95% CI, 26.8-52.8, <0.001) and the Walking Impairment Questionnaire distance score by +7.3 (95% CI, 2.4-12.1, =0.003). In all, 2828 individual Walking Impairment Questionnaire distance score questions were completed at baseline and follow-up. Among participants who perceived no change in ability to walk 1 or more distances between baseline and follow-up, 6-minute walk improved in the exercise group and declined in the control group (+26.8 versus -6.5 m, <0.001). Among participants who perceived that their walking ability worsened for 1 or more distances between baseline and follow-up, the 6-minute walk improved in the exercise group and declined in the control group (+18.4 versus -27.3 m, <0.001). Among participants who reported worsening calf symptoms at follow-up, the exercise group improved and the control group declined (+28.9 versus -12.5 m, <0.01). Conclusions In 3 randomized trials, exercise significantly improved the 6-minute walk distance in people with peripheral artery disease, but many participants randomized to exercise reported no change or decline in walking ability. These findings suggest a significant discrepancy in objectively measured walking improvement relative to perceived walking improvement in people with peripheral artery disease. Registration Information clinicaltrials.gov. Identifiers: NCT00106327, NCT01408901.
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http://dx.doi.org/10.1161/JAHA.120.017609DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Association of Hearing Impairment With Higher-Level Physical Functioning and Walking Endurance: Results From the Baltimore Longitudinal Study of Aging.

J Gerontol A Biol Sci Med Sci 2021 Sep;76(10):e290-e298

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Although hearing impairment (HI) is linked to poorer physical functioning, the longitudinal associations between HI and higher-level functional measures are unclear.

Method: Data are from the Baltimore Longitudinal Study of Aging (2012-2019). Using pure-tone audiometry, we categorized hearing into normal, mild, and moderate or greater HI. Physical function was assessed with the expanded Short Physical Performance Battery (eSPPB) and walking endurance with time to walk 400 m. Multivariable and mixed-effects linear models tested the hypotheses that participants with HI, at baseline, have poorer physical performance and walking endurance, and faster decline over time (up to 6 measurements). In a subset (n = 526), we further adjusted for vestibular function. Among participants with HI, we evaluated the differences in eSPPB scores and walking endurance between hearing aid users and nonusers.

Results: Of 831 participants, 26% had mild, and 17% moderate or greater HI. After adjustment for demographics and medical history, moderate or greater impairment versus normal hearing was associated with poorer function (0.17 [95% CI: 0.09, 0.26] lower eSPPB score, and 13.3 [95% CI: 3.31, 23.4] seconds slower 400-m walk time) and faster decline in these parameters over 6 years. Adjustment for vestibular function did not attenuate these associations. Hearing aid users walked 400 m 24 seconds faster than nonusers (p = .001).

Conclusion: Moderate or greater HI is associated with poorer initial and greater decline in higher-level physical performance. The observation that hearing aid users had better walking endurance suggests that screening for and treatment of HI may delay or slow progression of hearing-related functional decline.
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http://dx.doi.org/10.1093/gerona/glab144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436975PMC
September 2021

Fostering healthy aging: The interdependency of infections, immunity and frailty.

Ageing Res Rev 2021 08 7;69:101351. Epub 2021 May 7.

Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Stockholm Gerontology Research Center, Stockholm, Sweden.

Untangling the interdependency of infections, immunity and frailty may help to clarify their roles in the maintenance of health in aging individuals, and the recent COVID-19 pandemic has further highlighted such priority. In this scoping review we aimed to systematically collect the evidence on 1) the impact of common infections such as influenza, pneumonia and varicella zoster on frailty development, and 2) the role played by frailty in the response to immunization of older adults. Findings are discussed under a unifying framework to identify knowledge gaps and outline their clinical and public health implications to foster a healthier aging. Twenty-nine studies (113,863 participants) selected to answer the first question provided a moderately strong evidence of an association between infections and physical as well as cognitive decline - two essential dimensions of frailty. Thirteen studies (34,520 participants) investigating the second aim, showed that frailty was associated with an impaired immune response in older ages, likely due to immunosenescence. However, the paucity of studies, the absence of tools to predict vaccine efficacy, and the lack of studies investigating the efficacy of newer vaccines in presence of frailty, strongly limit the formulation of more personalized immunization strategies for older adults. The current evidence suggests that infections and frailty repeatedly cross each other pathophysiological paths and accelerate the aging process in a vicious circle. Such evidence opens to several considerations. First, the prevention of both conditions pass through a life course approach, which includes several individual and societal aspects. Second, the maintenance of a well-functioning immune system may be accomplished by preventing frailty, and vice versa. Third, increasing the adherence to immunization may delay the onset of frailty and maintain the immune system homeostasis, beyond preventing infections.
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http://dx.doi.org/10.1016/j.arr.2021.101351DOI Listing
August 2021

Association Between Walking Energetics and Fragmented Physical Activity in Mid- to Late-Life.

J Gerontol A Biol Sci Med Sci 2021 Sep;76(10):e281-e289

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Physical activity becomes increasingly fragmented with age, which may be an early marker of functional decline. Energetic cost of walking and energy capacity are also linked with functional decline, but their associations with activity fragmentation, and the potential modifying roles of total daily physical activity and age, remains unclear.

Method: A total of 493 participants (50-93 years) from the Baltimore Longitudinal Study of Aging underwent measures of energetic cost of usual-paced overground walking (mL/kg/m), energy demand during slow walking (mL/kg/min) on a treadmill (0.67 m/s, 0% grade), and average peak walking energy expenditure (mL/kg/min) during a fast-paced 400-m walk. A ratio of slow walking to peak walking energy expenditure ("cost-to-capacity ratio") was calculated. Activity fragmentation was quantified as an active-to-sedentary transition probability (ASTP) using Actiheart accelerometer data. Linear regression models with ASTP as the dependent variable were used to test whether poorer energy cost and capacity were associated with higher ASTP and whether the associations differed by daily physical activity or age.

Results: After adjusting for demographics, body composition, comorbidities, and daily physical activity, every 10% higher cost-to-capacity ratio was associated with 0.4% greater ASTP (p = .005). This association was primarily driven by the least active participants (pinteraction = .023). Peak walking energy expenditure was only associated with ASTP among participants aged ≥70 years.

Conclusions: Higher cost-to-capacity ratio and lower energy capacity may manifest as more fragmented physical activity, especially among those less active or aged ≥70 years. Future studies should examine whether an increasing cost-to-capacity ratio or declining energy capacity predicts subsequent activity fragmentation.
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http://dx.doi.org/10.1093/gerona/glab127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436987PMC
September 2021

A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice.

Elife 2021 Apr 20;10. Epub 2021 Apr 20.

Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States.

Aging is associated with distinct phenotypical, physiological, and functional changes, leading to disease and death. The progression of aging-related traits varies widely among individuals, influenced by their environment, lifestyle, and genetics. In this study, we conducted physiologic and functional tests cross-sectionally throughout the entire lifespan of male C57BL/6N mice. In parallel, metabolomics analyses in serum, brain, liver, heart, and skeletal muscle were also performed to identify signatures associated with frailty and age-dependent functional decline. Our findings indicate that declines in gait speed as a function of age and frailty are associated with a dramatic increase in the energetic cost of physical activity and decreases in working capacity. Aging and functional decline prompt organs to rewire their metabolism and substrate selection and toward redox-related pathways, mainly in liver and heart. Collectively, the data provide a framework to further understand and characterize processes of aging at the individual organism and organ levels.
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http://dx.doi.org/10.7554/eLife.62952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099423PMC
April 2021

Analysis of Hearing Loss and Physical Activity Among US Adults Aged 60-69 Years.

JAMA Netw Open 2021 04 1;4(4):e215484. Epub 2021 Apr 1.

Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Hearing loss may be a modifiable factor associated with decreased physical activity in older adults.

Objective: To examine the association of hearing loss with objectively measured physical activity, including moderate-to-vigorous physical activity, light-intensity physical activity, sedentary behavior, and pattern of physical activity (physical activity fragmentation).

Design, Setting, And Participants: This population-based cross-sectional study used National Health and Nutrition Examination Survey (NHANES) data collected in the 2003 to 2004 cycle and analyzed in 2017 to 2020. Participants aged 60 to 69 years with complete audiometry, physical activity, and comorbidity data were included in the analysis. Data analysis was performed from January 2017 to December 2020.

Exposures: Hearing defined by the pure tone average (PTA; range, 0.5-4 kHz) in the better ear, with normal PTA defined as less than 25 dB hearing loss, mild hearing loss defined as PTA 25 to less than 40 dB hearing loss, and moderate or greater hearing loss defined as a PTA greater than or equal to 40 dB hearing loss.

Main Outcomes And Measures: The primary outcomes were comprehensive metrics of objectively measured physical activity, including time spent in moderate-to-vigorous physical activity, light-intensity physical activity, and sedentary behavior, and physical activity fragmentation. Linear regression was used to model the association between hearing loss and physical activity.

Results: Of the 291 participants (mean [SD] age, 64.53 [2.96] years), 139 (47.8%) were male, 48 (16.5%) had mild hearing loss, and 22 (7.6%) had moderate or greater hearing loss. After adjusting for age, sex, education, race/ethnicity, and comorbidities, hearing loss (vs normal hearing) was significantly associated with less time spent in moderate-to-vigorous physical activity by 5.53 minutes per day (95% CI, -10.15 to -0.90 minutes per day), less time spent in light-intensity physical activity by 28.55 minutes per day (95% CI, -53.07 to -4.02 minutes per day), more time spent in sedentary behaviors by 34.07 minutes per day (95% CI, 8.32 to 59.82 minutes per day), and more fragmented physical activity pattern by 0.38 SD higher in active-to-sedentary transition probability (95% CI, to 0.10 to 0.65). The magnitude of the association of hearing loss (vs normal hearing) with physical activity metrics was equivalent to 7.28 years (95% CI, 3.19 to 11.37 years) of accelerated age for moderate-to-vigorous physical activity, 5.84 years (95% CI, 1.45 to 10.23 years) of accelerated age for light-intensity physical activity, and 10.53 years (95% CI, 2.89 to 18.16 years) of accelerated age for degree of physical activity fragmentation.

Conclusions And Relevance: These findings suggest that hearing loss is associated with a worse physical activity profile. Whether interventions to address hearing loss in adults could improve physical activity profiles will require further study.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056278PMC
April 2021

Visual Impairment and Objectively Measured Physical Activity in Middle-Aged and Older Adults.

J Gerontol A Biol Sci Med Sci 2021 Apr 10. Epub 2021 Apr 10.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Background: Vision loss is associated with increased falls risk and restricted physical activity, yet the relationship between multiple vision measures and objectively measured physical activity, especially activity patterns, in mid-to-late life is not well understood.

Methods: This study included 603 participants aged ≥ 50 years (mean age=73.5) in the Baltimore Longitudinal Study of Aging who had the following assessments: presenting and best-corrected visual acuity, contrast sensitivity, visual fields, stereo acuity, and free-living physical activity using a wrist-worn ActiGraph accelerometer for 7 days. Linear regression models were used to examine the association between vision measures and daily activity counts, active minutes, and activity fragmentation (defined as an active-to-sedentary transition probability), adjusting for potential confounders. Mixed-effects models estimated differences in activity by time of day comparing those with and without each visual impairment.

Results: In the fully adjusted model, worse presenting visual acuity, contrast sensitivity, and visual fields were associated with fewer activity counts, less active time, and more fragmented activity patterns (p<0.05 for all). Participants with presenting or best-corrected visual acuity impairment had 19.2 and 29.3 fewer active minutes (p=0.05, p=0.03, respectively) per day. Visual field impairment was associated with 268,636 fewer activity counts (p=0.02), 46.2 fewer active minutes (p=0.02) per day, and 3% greater activity fragmentation (p=0.009). Differences in activity levels tended to be greatest from 6am-6pm (p<0.05).

Conclusions: Older adults with visual impairment have restricted and more fragmented patterns of daily activity. Longitudinal studies to quantify the long-term impacts of visual impairments on activity decline are warranted.
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http://dx.doi.org/10.1093/gerona/glab103DOI Listing
April 2021

Age-associated expression of p21and p53 during human wound healing.

Aging Cell 2021 05 9;20(5):e13354. Epub 2021 Apr 9.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.

In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated β-galactosidase (SA-β-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects.
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http://dx.doi.org/10.1111/acel.13354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135007PMC
May 2021

Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: A systematic review and meta-analysis of phase III RCTs in Alzheimer's disease.

Ageing Res Rev 2021 07 5;68:101339. Epub 2021 Apr 5.

Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address:

Objective: To investigate the effects of monoclonal antibodies against Aβ on cognition, function, amyloid PET and other biomarkers, as well as risk for amyloid-related imaging abnormalities (ARIA) and other adverse events, in Alzheimer's disease (AD).

Methods: Pubmed, Web of Science, ClinicalTrials.gov and gray literature were searched for phase III RCTs and random-effects meta-analyses were performed.

Results: Seventeen studies (12,585 patients) were included. Antibodies statistically improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95 % CI (-0.10; -0.02), I = 0%]} and MMSE {SMD = 0.05 [95 % CI (0.01; 0.09), I = 0%]} by small effect sizes, but did not improve the cognitive/functional measure CDR-SOB {SMD = -0.03 [95 % CI (-0.07; 0.01), I = 18 %]}. Moreover, antibodies decreased amyloid PET SUVR {SMD = -1.02 [95 % CI (-1.70; -0.34), I = 95 %]} and CSF p181-tau {SMD = -0.87 [95 % CI (-1.32; -0.43), I = 89 %]} by large effect sizes. They also increased risk for ARIA {RR = 4.30 [95 % CI (2.39; 7.77), I = 86 %]} by a large effect size. Antibody effects on reducing amyloid PET SUVR were correlated with their effects on improving ADAS-Cog (r = +0.68, p = 0.02). In subgroup analyses by individual drug, Aducanumab improved ADAS-Cog, CDR-SOB, ADCS-ADL by small effect sizes and decreased amyloid PET SUVR and CSF p181-tau by large effect sizes. Solanezumab improved ADAS-Cog and MMSE by small effect sizes, and increased (improved) CSF Aβ levels by a moderate effect size. Bapineuzumab, Gantenerumab and Crenezumab did not improve any clinical outcomes. Bapineuzumab and Gantenerumab decreased CSF p181-tau by a small and large effect size, respectively. All drugs except Solanezumab increased ARIA risk.

Conclusions: In this meta-analysis of phase III trials in AD, we found that monoclonal antibodies against Aβ induced clinical improvements of small effect sizes, biomarker improvements of large effect sizes, and increases in risk for the hallmark adverse event, ARIA, by a large effect size, when all drugs were pooled together. Among individual drugs, Aducanumab produced the most favorable effects followed by Solanezumab. These findings provide moderate support for the continuous development of anti-Aβ monoclonal antibodies as a treatment for AD.
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http://dx.doi.org/10.1016/j.arr.2021.101339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161699PMC
July 2021

Sustained physical activity in peripheral artery disease: Associations with disease severity, functional performance, health-related quality of life, and subsequent serious adverse events in the LITE randomized clinical trial.

Vasc Med 2021 Apr 8:1358863X21989430. Epub 2021 Apr 8.

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle-brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85-6.54; < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67-6.46; < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34-1.28; < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs.
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http://dx.doi.org/10.1177/1358863X21989430DOI Listing
April 2021
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