| Biography: Dr. E. Jeffrey Metter received his M.D. from the University of California, Los Angeles in 1971. He completed a medical internship and neurology residency at the Mayo Graduate School of Medicine, Rochester, Minnesota in 1976. He returned to Los Angeles, where he became a staff neurologist and chief of the stroke rehabilitation ward at the Veterans Administration Medical Center, Sepulveda, California. He was also on the full time faculty in the Department of Neurology, UCLA School of Medicine. In 1987, he joined the National Institute on Aging as the physician for the Baltimore Longitudinal Study of Aging. |
| Prostate Aging and Disease: The Baltimore Longitudinal Study of Aging (BLSA) is characterizing normal aging in the prostate and identifying transitions to prostate disease, particularly benign prostatic hyperplasia (BPH) and prostate cancer. In addition, the research is using information about structure and function of the prostate to improve early detection of prostate disease. Clinical evaluations of prostate growth and function have been made in over 800 men with and without prostate disease and the availability of stored sera and genetic material. Prospectively, BLSA men aged from 30 to 79 have physiological assessment, clinical examination and imaging of their prostate. To date, the major accomplishments have come from analyses of prostate specific antigen (PSA) which show that PSA increases more over a period of years in men who develop BPH than in those who do not. The rate of change in PSA is even greater in men who develop prostate cancer, and the increases go up exponentially 5-7 years before diagnosis. Furthermore, the ratio of free to total PSA is able to distinguish men who develop prostate cancer from those who do not about 10 years before diagnosis. Analyses of a subset of the men who developed prostate cancer show that the free to total PSA ratio is lower in men who have clinically defined aggressive tumors. We have shown that normal levels of PSA can be used to stratify men at high risk of developing prostate cancer more than a decade before prostate cancer is diagnosed. Further, PSA levels and the rate of change in PSA over time can identify men at risk for high grade, potentially lethal prostate cancer 10 to 15 years before diagnosis of the cancer. Alterations in prostate structure or function are studied in relation to the possible development of prostate disease, particularly benign prostatic hyperplasia (BPH). Magnetic resonance imaging of the prostate was performed to estimate prostate volume as well as the percentage of epithelial and stromal tissue. Longitudinal evaluation of the prostate size found it to increase into the fifties and the rate of change declines in older age decades. Current research is examining the natural history of development of prostate symptomatology and risk factors for the development of BPH. Recently, we have found that obesity, elevated fasting plasma glucose, and diabetes are risk factors for BPH. Further, PSA was not a good indicator for the development of prostate symptomatology. |
| Neuromuscular Changes with Age: The purpose is to characterize and explain age associated losses of muscle strength. We seek to understand the time course of strength loss, factors that contribute to the loss, and to what degree the exercise response differs between old and young individuals. Our research currently has 3 main components: |
| 1. Characterization of Longitudinal Strength Changes in the BLSA: This consists of two parts. From 1960 to 1985, strength and power were measured in BLSA participants using in-house constructed equipment that measured isometric strength and power in the upper extremities. The purpose is to determine long-term longitudinal changes (up to 25 years) in strength and power, and to relate these changes to changes in muscle mass, peripheral nerve function, daily and physical activity, and aerobic fitness. Starting in 1992, strength has been measured using a state of the art isokinetic dynamometer (Kin-Com). This equipment allows for the measurement of both concentric and eccentric strength at multiple velocities in both the upper and lower extremities. The specific purposes are to determine age-associated maximal force production of the upper and lower body musculature during the concentric and eccentric phases of exertion, at fast, slow and zero speed, and determine the angle of greatest force; determine relationships between changes in strength with age and changes in lean body mass, fat mass, bone mineral density, glucose homeostasis, functional abilities, physical activity and nutritional state. We are also interested in the contribution of muscle strength to functional performance and the development of disability, balance problems, and falls. We have shown that the age-associated declines are explained in part by change in muscle mass. However, other factors are also important including changes in nerve function and hormonal levels (e.g. testosterone). Age-asssociated changes in strength are related to functional performance as demonstrated by an association with walking speed. However, in healthy individuals, a strength level is reached where no association is observed. This level implies the presence of excessive strength potential that acts as a reserve for walking performance. In addition, there is a complex relationship between muscle strength, muscle power, muscle mass and physical activity on mortality. We found that increasing muscle strength and power and how they change over time are long-term predictors of increased longevity, independent of how much muscle is present and how active you are. We believe, and are currently looking for evidence that age-associated changes in the central nervous system control of movement, is a key contributor to the relationships between strength, power and longevity. We have found that low muscle strength, muscle power, muscle mass, and slow movement speed are each independent predictors of mortality, arguing that both muscle and nervous system contributions to movement are important for survival. |
| 2. Exploratory Studies for Alternative Approaches to Exercise: We have been interested in finding alternative strategies that can be used to maintain muscle integrity and strength. Resistive and aerobic training can help to improve performance in the elderly. However, these are typically supervised activities that require attendance at specific sites or venues. Such activities, while beneficial, are not ideal for all individuals. Therefore, alternative approaches are needed in order to offer an array of opportunities for exercising. We have focused on examining subjects with osteoarthritis of the knee. This group of individuals tends to be sedentary and do very little physical activity. In a pilot study, we examined two approaches to encourage increased activity. First, we examined the use of a pedometer to act as a motivator for walking. We found improvements in how much walking subjects did on a routine basis over a 12 week period. The second approach was the use of a home-based, self-administered electromyostimulation of the thigh muscle in order to strengthen the muscle. The protocol generated up to 40% of the maximal force that subjects were able to generate in extending their knee. This level of stimulation is well tolerated and subjects continued to use the equipment at home over the course of the study. Over a 12 week period, we found significant improvements in muscle strength. At present, we are examining the use of the pedometer in the National Guard for individuals who fail their physical fitness test, and are planning further studies to explore the use of electromyostimulation. |
| 3. Examination of the Motor Unit and Its Relationship to Muscle Strength and Exercise Response: A clinical protocol has been developed that explores motor unit function at different levels of muscle exertion in the quadriceps. The goal of this project is to understand the changes that occur in motor units with aging, and the effects of these changes on muscle strength and how these changes affect the exercise response. Over the past 20 years in vivo techniques allow for the direct examination of the motor units in humans. Most studies that have examined age-related changes in motor units have focused on old versus young rather than examining the entire adult lifespan. They do not allow for an assessment of where during the lifespan these changes begin, or the association between the motor units and strength. We have developed a clinical protocol that allows for the evaluation of motor units during the generation of fixed force levels. We have found a strong relationship between the size and firing rates of motor units and force generation. With resistance training, smaller units are able to generate fixed forces in the absence of improved strength to a nontraining task. We are now examining changes with age in the BLSA. |
| Age-Associated Race and Gender Differences in the Carotid and Intracerebral Arteries: This project examined intracerebral blood flow velocity and resistance, carotid blood flow velocity, and carotid wall characteristics using doppler ultrasonographic techniques in BLSA participants. The goal is to determine whether differences in either carotid or intracerebral parameters may explain racial and gender differences in stroke and coronary heart disease, and whether changes in arterial characteristics are associated with fitness and frailty. We have found that intimal-media thickness of the common carotid artery increases with age concomitant with dilitation. Greater carotid wall thickness is associated with increasing risk for the development of both overt and silent coronary heart disease after adjusting for age, and common carotid wall thickness is thicker in the presence of asymptomatic coronary disease. Carotid doppler ultrasonography is commonly used during evaluation of cerebrovascular disease. Our findings suggest that examining the carotid wall thickness can increase the suspicion for coronary artery disease. In a related analysis, we found that women who use estrogen replacement postmenopausally show less arterial stiffness than women who are not on replacement. We have also observed that age change in flow velocities in the carotid artery is poorly correlated with the flow velocities in the middle cerebral arteries. We have compared different measures of arterial stiffness across age and explored which measures are most related to the development of coronary heart disease. Recently, we examined the impact of alcohol use, and serum androgen levels on arterial stiffness. We found that both moderate alcohol usage and higher serum testosterone have a positive impact with lower arterial stiffness. |
| Recent Publications: |
- Carter HB, Ferrucci L, Kettermann A, Landis P, Wright EJ, Epstein JI, Trock BJ, Metter EJ. Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. J. Natl. Cancer Inst. 98(21): 1521-1527, 2006.
- Martel GF, Roth SM, Ivey FM, Lemmer JT, Tracy BL, Hurlbut DE, Metter EJ, Hurley BF, Rogers MA. Age and sex affect muscle fibre adaptations to heavy resistance strength training. Exp. Physiol. 91(2): 457-464, 2006.
- Parsons JK, Carter HB, Partin AW, Windham BG, Metter EJ, Ferrucci L, Landis P, Platz EA. Metabolic factors associated with benign prostatic hyperplasia. J. Clin. Endocrinol. Metab. 91(7): 2562-2568, 2006.
- Metter EJ, Schrager M, Ferrucci L, Talbot LA. Evaluation of movement speed and reaction time as predictors of all-cause mortality in men. J. Gerontol. A Biol. Sci. Med. Sci. 60(7): 840-846, 2005.
- Parsons JK, Carter HB, Platz EA, Wright EJ, Landis P, Metter EJ. Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Cancer Epidemiol. Biomarkers Prev. 14(9): 2257-2260, 2005.
- Conwit RA, Ling S, Roth S, Stashuk D, Hurley B, Ferrell R, Metter EJ. The relationship between ciliary neurotrophic factor (CNTF) genotype and motor unit physiology: preliminary studies. BMC Physiol. 5(1): 15, 2005.
- Hougaku H, Fleg JL, Lakatta EG, Scuteri A, Earley CJ, Najjar S, Deb S, Metter EJ. Effect of light-to-moderate alcohol consumption on age-associated arterial stiffening. Am. J. Cardiol. 95(8): 1006-1010, 2005.
- Hubbard JS, Rohrmann S, Landis PK, Metter EJ, Muller DC, Andres R, Carter HB, Platz EA. Association of prostate cancer risk with insulin, glucose, and anthropometry in the Baltimore Longitudinal Study of Aging. Urology. 63(2): 253-258, 2004.
- Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM. Free testosterone and risk for Alzheimer disease in older men. Neurology. 62(2): 188-193, 2004.
- Ryan AS, Ivey FM, Hurlbut DE, Martel GF, Lemmer JT, Sorkin JD, Metter EJ, Fleg JL, Hurley BF. Regional bone mineral density after resistive training in young and older men and women. Scand. J. Med. Sci. Sports. 14(1): 16-23, 2004.
- Metter EJ, Talbot LA, Schrager M, Conwit RA. Arm-cranking muscle power and arm isometric muscle strength are independent predictors of all-cause mortality in men. J. Appl. Physiol. 96(2): 814-821, 2004.
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