1Insulin resistance increases and muscle oxidative capacity decreases during aging, but lifestyle changesespecially physical activity-may reverse these trends. Here we report the effect of a 16-week aerobic exercise program (n ‫؍‬ 65) or control activity (n ‫؍‬ 37) performed by men and women aged 21-87 years on insulin sensitivity and muscle mitochondria. Insulin sensitivity, measured by intravenous glucose tolerance test, decreased with age (r ‫؍‬ ؊0.32) and was related to abdominal fat content (r ‫؍‬ ؊0.65). Exercise increased peak oxygen uptake (VO 2peak ; 10%), activity of muscle mitochondrial enzymes (citrate synthase and cytochrome c oxidase, 45-76%) and mRNA levels of mitochondrial genes (COX4, ND4, both 66%) and genes involved in mitochondrial biogenesis (PGC-1␣, 55%; NRF-1, 15%; TFAM, 85%). Exercise also increased muscle GLUT4 mRNA and protein (30 -52%) and reduced abdominal fat (5%) and plasma triglycerides (25%). None of these changes were affected by age. In contrast, insulin sensitivity improved in younger people but not in middle-aged or older groups. Thus, the muscle mitochondrial response to 4 months of aerobic exercise training was similar in all age-groups, although the older people did not have an improvement in insulin sensitivity. Diabetes 52: 1888 -1896, 2003 T he number of people with type 2 diabetes and impaired glucose tolerance is rapidly increasing (1,2). Key factors contributing to this increase in diabetes include age, obesity, and sedentary lifestyle (3-8). Exercise is a readily available intervention that can increase insulin action (9 -14) and prevent the onset of diabetes (15-18). An important question is whether the effects of aerobic exercise on insulin action are diminished with advancing age. A recent study reported that a vigorous 7-day exercise program increased insulin sensitivity and muscle glucose transporter (GLUT4) content by a similar amount in younger (22 years) and older (61 years) people (12). However, current health and fitness guidelines for healthy adults recommend exercising at more moderate intensities at least 3 days per week over long periods (19). Thus, the first purpose of the current study was to determine whether a 4-month program of bicycle training that could be readily followed by most elderly individuals would lead to a similar improvement in insulin sensitivity in men and women across a wide age span.Skeletal muscle is the major site of insulin-mediated glucose disposal and is implicated in the pathogenesis of insulin resistance and diabetes (20,21). Several pieces of evidence suggest that insulin action may be related to the oxidative capacity of skeletal muscle. First, aerobic exercise training improves both insulin sensitivity and activity of oxidative enzymes in muscle (22,23). Second, people who are obese and insulin resistant or have type 2 diabetes tend to have lower activity of muscle oxidative enzymes (24,25). Third, insulin infusion preferentially stimulates the synthesis rate of mitochondrial proteins in skeletal muscle (26) and increa...

.-Aging in humans is associated with loss of lean body mass, but the causes are incompletely defined. Lean tissue mass and function depend on continuous rebuilding of proteins. We tested the hypotheses that whole body and mixed muscle protein metabolism declines with age in men and women and that aerobic exercise training would partly reverse this decline. Seventy-eight healthy, previously untrained men and women aged 19-87 yr were studied before and after 4 mo of bicycle training (up to 45 min at 80% peak heart rate, 3-4 days/wk) or control (flexibility) activity. At the whole body level, protein breakdown (measured as [13 C]leucine and [ 15 N]phenylalanine flux), Leu oxidation, and protein synthesis (nonoxidative Leu disposal) declined with age at a rate of 4-5% per decade (P Ͻ 0.001). Fat-free mass was closely correlated with protein turnover and declined 3% per decade (P Ͻ 0.001), but even after covariate adjustment for fat-free mass, the decline in protein turnover with age remained significant. There were no differences between men and women after adjustment for fat-free mass. Mixed muscle protein synthesis also declined with age 3.5% per decade (P Ͻ 0.05). Exercise training improved aerobic capacity 9% overall (P Ͻ 0.01), and mixed muscle protein synthesis increased 22% (P Ͻ 0.05), with no effect of age on the training response for either variable. Fat-free mass, whole body protein turnover, and resting metabolic rate were unchanged by training. We conclude that rates of whole body and muscle protein metabolism decline with age in men and women, thus indicating that there is a progressive decline in the body's remodeling processes with aging. This study also demonstrates that aerobic exercise can enhance muscle protein synthesis irrespective of age. leucine; phenylalanine; amino acid kinetics; resting metabolic rate; fractional synthesis rate; aging AGING IN HUMANS is associated with alterations in body composition, leading to a loss of lean tissue and a corresponding gain in body fat (34,35). This shift in body composition is considered a risk factor for disease and disability, yet the mechanisms for lean tissue loss in older persons are not yet fully understood. The quantity of lean tissue mass depends on protein turnover and the balance between protein synthesis and breakdown. Protein kinetics at the level of the whole body, body regions, or individual tissues can be readily measured in vivo with the use of labeled amino acid tracers (24). Although these methods have been used to determine whether protein metabolism is altered with aging, several questions remain.Several studies have compared whole body protein turnover data in younger and older people (Table 1) but have provided widely mixed results. At least three factors may account for these varied outcomes. First, some studies have relied on small sample sizes, often comparing eight or fewer people grouped as "young" and "old" (7,11,12,14,15,23,33,45,49,51). Unless the variability among people is small, there may not be adequate power to detect a ...

Glucose tolerance decreases with age. For determining the cause of this decrease, 67 elderly and 21 young (70.1 ؎ 0.7 vs. 23.7 ؎ 0.8 years) participants ingested a mixed meal and received an intravenous injection of glucose. Fasting glucose and the glycemic response above basal were higher in the elderly than in the young participants after either meal ingestion (P < 0.001) or glucose injection (P < 0.01). Insulin action (Si), measured with the meal and intravenous glucose tolerance test models, was highly correlated (r ‫؍‬ 0.72; P < 0.001) and lower (P < 0.002) in the elderly than in the young participants. However, when adjusted for differences in percentage body fat and visceral fat, Si no longer differed between groups. When considered in light of the degree of insulin resistance, all indexes of insulin secretion were lower (P < 0.01) in the elderly participants, indicating impaired ␤-cell function. Hepatic insulin clearance was increased (P < 0.002), whereas total insulin clearance was decreased (P < 0.002) in the elderly subjects. Multivariate analysis (r ‫؍‬ 0.70; P < 0.001) indicated that indexes of insulin action (Si) and secretion (Phi total ) but not age, peak oxygen uptake, fasting glucose, degree of fatness, or hepatic insulin clearance predicted the postprandial glycemic response. We conclude that the deterioration in glucose tolerance that occurs in healthy elderly subjects is due to a decrease in both insulin secretion and action with the severity of the defect in insulin action being explained by the degree of fatness rather than age per se. Diabetes

Neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life. (ClinicalTrials.gov number, NCT00254371 [ClinicalTrials.gov].).

The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.

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Aging is associated with reduced muscle strength and atrophy of type II muscle fibers. Muscle fiber type and contractile function are primarily determined by myosin heavy chain (MHC) isoforms. There are few data available on the effects of aging on MHC isoform expression in humans. In the present study, we tested the hypothesis that MHC isoform protein composition and mRNA abundance would favor a fast-to-slow isoform shift with aging and in response to endurance exercise training. Muscle biopsies were obtained from previously sedentary, healthy men and women, aged 21-87 yr before (n = 77) and after (n = 65) 16 wk of bicycle training (up to 45 min at 80% peak heart rate, 3-4 days/wk). At baseline, MHC I mRNA was unchanged with age, whereas IIa and IIx declined by 14 and 10% per decade, respectively (P < 0.001). MHC IIa and IIx protein declined by 3 and 1% per decade with a reciprocal increase in MHC I (P < 0.05). After training, MHC I and IIa mRNA increased by 61 and 99%, respectively, and IIx decreased by 50% (all P < 0.001). The increase in MHC I mRNA was positively associated with age, whereas the changes in MHC IIa and IIx mRNA were similar across age. MHC I protein increased by 6% and was positively related to age, whereas IIx decreased by 5% and was inversely related to age. These results suggest that the altered expression of MHC isoforms with aging is transcriptionally regulated. In response to endurance exercise, regulation of MHC isoform transcripts remains robust in older muscle, but this did not result in corresponding changes in MHC protein expression.

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