The Effect of the Human Brainstem Myelination on Gait Speed in Normative Aging.

The brainstem functions as a relay and integrative brain center and plays an essential role in motor function. Whether brainstem tissue deterioration, including demyelination, affects motor function has not been studied. Understanding the potential relationship between brainstem demyelination and motor function may be useful for the early diagnosis of neurodegenerative diseases and to understand age-related gait impairments that have no apparent cause. In this work, we investigated the associations between rapid or usual gait speeds, as integrative measures of motor function, and cerebral myelin content. In 118 individuals (age 22-94 years) free of neurodegenerative diseases or cognitive impairment, myelin content was assessed as the myelin water fraction, a direct magnetic resonance imaging measure of myelin content, and longitudinal and transverse relaxation rates (R1 and R2), which are sensitive magnetic resonance imaging measures of myelin content. Our results indicate that participants with lower usual or rapid gait speed exhibited lower values of myelin water fraction and R1 in the main brainstem regions, which were more evident and statistically significant in the midbrain. In contrast, we found no significant associations between gait speeds and R2, an expected result because various physiological factors confound R2. These original findings provide evidence that the level of brainstem myelination may affect gait performance among cognitively unimpaired adults who are free from any clinically detectable neurodegenerative diseases. Further studies are needed to understand the longitudinal changes in brainstem myelination with aging and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Transcriptomes of human primary skin fibroblasts of healthy individuals reveal age-associated mRNAs and long noncoding RNAs.

Changes in the transcriptomes of human tissues with advancing age are poorly cataloged. Here, we sought to identify the coding and long noncoding RNAs present in cultured primary skin fibroblasts collected from 82 healthy individuals across a wide age spectrum (22-89 years old) who participated in the GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing) study of the National Institute on Aging, NIH. Using high-throughput RNA sequencing and a linear regression model, we identified 1437 coding RNAs (mRNAs) and 1177 linear and circular long noncoding (lncRNAs) that were differentially abundant as a function of age. Gene set enrichment analysis (GSEA) revealed select transcription factors implicated in coordinating the transcription of subsets of differentially abundant mRNAs, while long noncoding RNA enrichment analysis (LncSEA) identified RNA-binding proteins predicted to participate in the age-associated lncRNA profiles. In summary, we report age-associated changes in the global transcriptome, coding and noncoding, from healthy human skin fibroblasts and propose that these transcripts may serve as biomarkers and therapeutic targets in aging skin.

Proteomes of primary skin fibroblasts from healthy individuals reveal altered cell responses across the life span.

Changes in the proteome of different human tissues with advancing age are poorly characterized. Here, we studied the proteins present in primary skin fibroblasts collected from 82 healthy individuals across a wide age spectrum (22-89 years old) who participated in the GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing) study of the National Institute on Aging, NIH. Proteins were extracted from lysed fibroblasts and subjected to liquid chromatography-mass spectrometry analysis, and the expression levels of 9341 proteins were analyzed using linear regression models. We identified key pathways associated with skin fibroblast aging, including autophagy, scavenging of reactive oxygen species (ROS), ribosome biogenesis, DNA replication, and DNA repair. Changes in these prominent pathways were corroborated using molecular and cell culture approaches. Our study establishes a framework of the global proteome governing skin fibroblast aging and points to possible biomarkers and therapeutic targets.

Skeletal muscle ex vivo mitochondrial respiration parallels decline in vivo oxidative capacity, cardiorespiratory fitness, and muscle strength: The Baltimore Longitudinal Study of Aging.

Mitochondrial function in human skeletal muscle declines with age. Most evidence for this decline comes from studies that assessed mitochondrial function indirectly, and the impact of such deterioration with respect to physical function has not been clearly delineated. We hypothesized that mitochondrial respiration in permeabilized human muscle fibers declines with age and correlates with phosphocreatine postexercise recovery rate (kPCr), muscle performance, and aerobic fitness. Mitochondrial respiration was assessed by high-resolution respirometry in saponin-permeabilized fibers from vastus lateralis muscle biopsies of 38 participants from the Baltimore Longitudinal Study of Aging (BLSA; 21 men, age 24-91 years) who also had available measures of peak oxygen consumption (VO2max ) from treadmill tests, gait speed in different tasks, 31 P magnetic resonance spectroscopy, isokinetic knee extension, and grip strength. Results indicated a significant reduction in mitochondrial respiration with age (p < .05) that was independent of other potential confounders. Mitochondrial respiratory capacity was also associated with VO2max , muscle strength, kPCr, and time to complete a 400-m walk (p < .05). A negative trend toward significance (p = .074) was observed between mitochondrial respiration and BMI. Finally, transcriptional profiling revealed a reduced mRNA expression of mitochondrial gene networks with aging (p < .05). Overall, our findings reinforce the notion that mitochondrial function declines with age and may contribute to age-associated loss of muscle performance and cardiorespiratory fitness.