The Baltimore Longitudinal Study of Aging (BLSA) prostate aging and disease study has both retrospective and prospective arms involving repeated assessments of anatomical, physiological, hormonal, and behavioral aspects of age-associated changes in prostate size. The retrospective arm of the study examines the sex steroid and PSA levels from frozen sera stored during the three most recent visits and visits closest to 10, 15, 20 and 25 years before study initiation. The prospective arm involves male BLSA participants and has continued for more than 15 years. Data collection was on hold starting in December 2002, and was restarted in approximately August 2005. [unreadable] Our previous work suggests that prostate cancer develops over a period of at least 10 years in most men, and that PSA can stratify men at risk as long as 20 to 30 years prior to diagnosis. These observations argue that there is a long period in the development of prostate cancer, where preventive strategies might decrease the risk for prostate cancer and perhaps for better identifying men where the prostate cancer might be life threatening. [unreadable] Recent work has focused on identifying men who develop life threatening prostate cancer that can be detected during clinical evaluation at a time when the cancer should be curable. Prostate specific antigen (PSA) is widely used to screen for prostate cancer because cancers detected by PSA screening are discovered at an earlier stage than without screening. Clinicians generally agree that PSA screening can detect early stage cancers and that some of these are destined to metastasize. However, the PSA level or threshold value at which further evaluation with a prostate biopsy should be recommended remains controversial. A major concern with the use of PSA for early diagnosis, or as a risk factor for future prostate cancer diagnosis is the likelihood that the identified cancer will be low grade and would never threaten the well-being or life of the individual man. Recent work by DAmico et al has suggested that a large PSA velocity within the year before cancer diagnosis is associated with a strong likelihood of a life-threatening cancer. However, the likelihood of curing such a prostate cancer would be low. We asked whether PSA velocity could be used to identify men who subsequently died of prostate cancer 10 or more years before the actual diagnosis of their prostate cancer. We found that PSA velocity had a relative risk for having a life-threatening prostate cancer of approximately 4.0 (1.2-12.9) per ng/ml/yr increase. PSA velocity measured 10-15 years before diagnosis predicted cancer-specific survival 25 years later. As compared to those with a PSA velocity <0.35ng/ml per year, the relative risk of prostate cancer death was 4.7 (95% CI = 1.3 to 16.5) when PSA velocity was >0.35ng/ml per year. These observations suggest that at a time when PSA levels indicate the presence of curable prostate cancer, PSA velocity may help identify men with life threatening disease.[unreadable] Currently, we are extending this concept by asking whether using a mans cumulative PSA history can improve the assessment of future risk of having a life-threatening prostate cancer. Using a simple additive approach where at each evaluation the health care provider sums the number of PSA evaluations where the patient has met a simple rule, the probability of having or developing a life threatening prostate cancer can be estimated. For example, a man over the age of 40 who never meets the rule of having a PSA velocity greater than 0.2 mg/year, will have approximately a 2-4% probability of developing a life-threatening prostate cancer, while a man who has met this rule on 5 consecutive yearly evaluations has a risk of 19% (CI=8-35%), despite the likelihood that his PSA is still quite normal. We are currently examining this concept further using simulation models.[unreadable] Another concern in relationship to prostate cancer is whether screening is appropriate and for which men and at what age. There is currently no general agreement on who should be screened and when. Little work has been directed at the question of when to stop screening if it is being done. We are currently addressing this question in relationship to the identification of life- threatening prostate cancer. In our analyses, we find that men older than 75 years with a PSA less than 3 ng/ml have essentially zero risk of subsequently developing a life threatening prostate cancer. Thus, stopping PSA is a low risk procedure in this older age group.[unreadable] A second area of interest is benign prostatic hyperplasia (BPH) is a common problem affecting more than 90% of men by the age of 80 years. The causes of growth in the gland are multifactorial and are directly related to androgenic hormones. BPH is a major health problem requiring treatment in more than 25% of men. We have been interested in the natural history of prostate growth, and in understanding the association between aging, prostate growth and the development of BPH and symptoms. Over the past year, we examined the relationships of obesity and associated abnormalities in glucose homeostasis with benign prostatic hyperplasia development. We found that obesity, elevated fasting plasma glucose concentration, and diabetes are associated with radiologically determined prostate enlargement, an objective measure of BPH. Recently, we have been examining the relationship of prostate size, change in size and PSA blood levels. This becomes an important consideration when evaluating whether a man does or does not have prostate cancer. While this work is still in process, it appears that a relationship between changing PSA levels and changes in prostate size may only occur in the presence of an enlarging gland. [unreadable] At this time, we are continuing to examine factors that contribute to prostate growth and the development of cancer, and strategies for early diagnosis of prostate disease with a focus on the identification of risk for high risk cancers. In the coming year, we are planning an examination of a new marker for prostate cancer, and to begin a study of the genetic characteristics for the development of high risk prostate cancer.