OFAS: 1997 Report of the Director

REPORTS AVAILABLE: 1993 (30 ^th Anniversary) 1997

1997 Annual Report:

Report of the Director

Even the most innovative ideas are worth little until communicated. Science is the realm of ideas and facts, so communication in this field is crucial. Thus, scientists have developed diverse ways to exchange ideas with their peers in the lab down the hall, across campus, and around the world. Equally important is to distribute knowledge to science's beneficiaries, the public.

Every year staff members participate in conferences and symposia, presenting results from OFAS research and gathering new information from other researchers in fields of mutual interest. Every day, staff utilize the information available in our extensive library, accessing scholarly journals and texts, the long-time mainstays of scientific communication, and use the vast computer databases of the National Library of Medicine.

Scientists know that pre-publication peer-review of papers is integral to ensuring the validity of scientific research. OFAS is honored that our specifically expert staff are regularly asked to peer-review manuscripts for a variety of journals. Also, OFAS is proud to house the Editorial Office of Steroids, managing the flow of manuscripts through the review process for this prestigious journal.

Perhaps the greatest and most productive example of communication among scientists is the collaborative study. OFAS has ten such studies in progress with partners around the world. These projects, in particular, allow the sharing of resources, such as the OFAS Serum Treasury, and the free exchange of ideas between institutions. Such collaborations speed achievement of the OFAS goal of developing interventions that prevent, halt, or reverse those disorders that decrease the quality or length of life.

Conferences, lectures, symposia, journals, internet chats, television -- all help to collect and disseminate the ever-growing body of scientific knowledge. This Report focuses on how OFAS gathers and disperses information within the scientific community and beyond, while providing an update on our current projects and results.

Norman Orentreich, MD, FACP

Presentations and Lectures

58^th Annual Meeting of the Society for Investigative Dermatology Washington, DC April 23-27, 1997	This meeting assembles lectures and poster presentations on the most up-to-date research in the field of dermatologic science and is an excellent opportunity for attendees to exchange concepts for further research. OFAS staff presented two posters and acquired many new ideas that are directly related to our research, on such topics as: alopecia areata, programmed cell death in hair follicles, testosterone metabolism, new and selective antiandrogens, 5alpha-reductase inhibition, and retinoic acid.
The same growth factors that are involved in wound healing also modulate phases of the hair cycle and hair production.	Yang J, Argawal P, Orentreich N. In vitro IGFs and bFGF upregulate human hair follicles respectively through follicular stem cells and papilla cells (abstract). J Invest Dermatol 108(4): 621
This novel and animal-friendly assay allows researchers to use hamsters to evaluate anti-androgens with neither distress nor anesthesia for the hamsters.	Brind J, Lemon LJ, Malloy VL, Orentreich N. A non-invasive method for assessing antiandrogenic activity on the ear sebaceous gland of the Syrian golden hamster (abstract). J Invest Dermatol 108(4): 655.
1^st Annual International Symposium on Aging Skin San Diego Bay, CA February 20-21, 1997	OFAS Director Norman Orentreich was invited to lecture on "Hormone Supplementation for Aging", in particular because of the extensive contributions by OFAS to knowledge of DHEA/DHEAS. The lecture was later expanded into a paper for the Journal of Geriatric Dermatology. The article reviews how biologic age can be measured, OFAS's work in establishing measures of age, the periodic nature of aging, and the decline of DHEAS levels including the establishment of a standard aging curve for DHEAS. Also covered are studies on oral and topical supplementation with DHEA, and topical testosterone therapy for men and women.

Conferences

3^rd International Symposium on Neurobiology & Neuroendocrinology of Aging Bregenz, Austria July 21-26, 1996	Age-related changes in the complex interaction between the neural and endocrine systems were examined at both the molecular and organismal levels. That these changes are genetically programmed is supported by the telomere theory of aging and by the discovery of life-span controlling genes in the nematode C. elegans. However, evidence for the role of environmental factors includes the damage by free radicals, which suggests that anti-oxidants may help to preserve neurobiologic function. OFAS is working with New York University Medical Center on normal and demented brain metabolism of glucose and insulin.
2^nd Meeting on Animal Models - Joint Conference with the Hair Research Society Bar Harbor, ME September 24-28, 1996	The Jackson Laboratory, sponsor of this workshop, is one of the largest breeders of mutant mice models for biomedical research on human diseases. This meeting focused on mouse models to study hair follicle development, hair formation, and many adult and pediatric human hair disorders. Some years ago, OFAS bred its own unique mouse model for androgenetic alopecia, which progressively develops baldness in response to androgens, a model of considerable interest to the research community.
36^th Annual Meeting of the Society for Cell Biology San Francisco, CA December 7-11,1996	A current area of widespread interest in the inherent behavior of cells is apoptosis, the pre-programmed death of cells. Of particular interest to OFAS is how this process, via its various chemical signaling messengers, is related to the programmed cycling of growth and rest of the hair follicle.
American Association for Anti-Aging Meeting Las Vegas, NV December 12-16, 1996	The new specialty of anti-aging medicine acknowledges aging as a disorder amenable to intervention. The need for establishing biomarkers of aging in order to assess the efficacy of treatments (e.g., growth hormone replacement, anti-oxidant supplementation, melatonin, etc.) was emphasized. DHEAS's role as a biomarker of aging, based upon pioneering work at OFAS, was explored along with the benefits and potential negatives of DHEA supplementation.
Cutaneous Malignancies Bethesda, MD June 10-11, 1997	A major effort in developing immunotherapy for cutaneous malignancies, melanoma in particular, involves indentification of tumor proteins (antigens) that are attacked by the patient's immune system. Once known, these proteins may potentially be used as vaccines or for passive transfer of immunity to patients by sensitizing blood lymphocytes to them in vitro prior to infusion. Several recently isolated antigens are now being used in clinical trials. Expression of these antigens by tumor cells may sensitize patients to normal melanocytes, resulting in a high incidence of vitiligo among melanoma sufferers. These antigens can be tested in our vitiligo mouse model; given orally, they may induce tolerance.
79^th Annual Endocrine Society Meeting Minneapolis, MN June 11-14, 1997	One focus of this meeting was Metabolic Syndrome (also known as Insulin Resistance Syndrome or Syndrome X), the importance of which has been underscored by the recent FDA approval of troglitazone, the first drug shown to increase insulin sensitivity. A large segment of the population is undiagnosed as pre-diabetic with hyperinsulinemia, the long-term adverse effects of which include coronary artery disease, obesity, and evolution to non-insulin dependent diabetes. OFAS is studying the role of hyperinsulinemia in hairloss as well as the role of insulin resistance in Alzheimer's disease.
46^th Annual Symposium on the Biology of the Skin Aging of the Skin: Basic mechanisms and approaches to prevention Snowmass, CO July 19-24, 1997	Recently, science has provided molecular insight into the mechanism of adverse effects of UV radiation on human skin. UV rays initiate a cascade of events in the skin, activating damaging enzymes and inflammatory cytokines that disorder the major structural components of skin, collagen and elastin, as well as pigment. Prevention and reversal of these effects can now be approached more precisely with, for example, specific enzyme inhibitors and anti-inflammatory compounds. Skin exposure to UV light has an important benefit, however; it stimulates vitamin D production by the skin. Therefore, regular use of sunscreens requires increased dietary vitamin D.

Publications

Denotes studies using the OFAS Serum Treasury

Risk for gastric lymphoma in persons with CagA positive and CagA negative Helicobacter pylori infection. Journal of Infectious Diseases, in press. HL Witherell, S Hansen, E Jellum, N Orentreich, JH Vogelman, J Parsonnet		.
.	This particular strain of H. pylori bacteria does not significantly alter the risk of developing gastric lymphoma.
Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer's disease. Journal of Clinical Endocrinology and Metabolism 62:3251-3258, 1997. MJ de Leon, T McRae, H Rusinek, A Convit, S De Santi, C Tarshish, J Colomb, N Volkiw, K Daisley, N Orentreich, B McEwen		.
.	The integrity of the hippocampus is necessary for normal memory function. Stress hormones such as cortisol reduce glucose metabolism in the hippocampus, making more available in the blood for 'fight or flight'. Persons with Alzheimer's Disease don't show this normal response.
Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 40:297-301, 1997. J Parsonnet, GD Friedman, N Orentreich, JH Vogelman		.
.	Persons with gastric cancer are 3.2-fold more likely to have had CagA positive strain infection.
Hormone supplementation (adapted from the First Annual International Symposium on Aging Skin). Journal of Geriatric Dermatology 5: 220-224, 1997. N Orentreich		.
.	This paper is summarized above.
5alpha-Reductase activity and prostate cancer: A case-control study using stored sera. Cancer Epidemiology, Biomarkers & Prevention 6: 21-24, 1997. HA Guess, GD Friedman, MC Sadler, FZ Stanczyk, JH Vogelman, J Imperato-McGinley, RA Lobo, N Orentreich		.
.	This study found no correlation between the incidence of prostate cancer and the levels of 5alpha-reduced androgens such as DHT, but 5alpha-reductase activity in the prostate itself may still play a role.
Dehydroepiandrosterone sulfate (DHEAS), angina, and fatal ischemic heart disease (Abstract). American Journal of Epidemiology 143: S69, 1996. CA Schaefer, G Friedman, B Ettinger, C Quesenbury, J Liu, M Haan, N Orentreich, J Vogelman		.
.	DHEAS levels are positively associated with smoking, alcohol consumption, elevated serum glucose, and total cholesterol in men, but not with body mass or central obesity; it is negatively associated with angina and fatal ischemic heart disease. There was no relationship found between DHEAS and fatal or non-fatal heart disease for women.
Dehydroepiandrosterone and risk of dementia in men (abstract). Neuroepidemiology 15: 9, 1996. C Schaefer, G Friedman, B Ettinger, C Quesenbury, N Orentreich, J Vogelman		.
.	Although higher levels of DHEAS were found to be associated with a lower incidence of dementia in men, no protective effect was seen in women.

Television

Forever Young
Zweite Deutsche Fernsehen
Munich, Germany

W5: Fountain of Youth
CTV Television Network, Ltd.
Toronto, ON, Canada

OFAS Director Norman Orentreich was interviewed for these two programs on anti-aging strategies. Broadcast throughout Europe and Canada, respectively, they provided up-to-date information in terms readily understood by the lay public. He focused on hormone decreases with aging and individualized "hormone cocktail" therapy. Other interviewees [William Regelson (Medical College of Virginia), William Haseltine (Human Genome Sciences), Gwen Ivy (University of Toronto) and Reubin Andres (NIH/NIA)] discussed melatonin, gene therapy, anti-oxidant therapy, and the famous Baltimore Longitudinal Study of Aging.

Collaborative Studies in Progress

Denotes studies using the OFAS Serum Treasury	OFAS in collaboration with
Prostate cancer and male hormone levels: Influence of religious or secular lifestyle	Hadassah Medical Organization
Hemochromatosis (a disorder of excess iron accumulation) and the genetic predisposition to liver disease	Kaiser Permanente Division of Research
DHEAS and DHT: Their contribution to mortality differences in 1,948 men and women aged 50 and over	Hadassah Medical Organization
Can DNA reliably be found in serum samples	Kaiser Permanente Division of Research
Insulin resistance in persons with Alzheimer's disease	New York University School of Medicine
Association of non-Hodgkin's lymphoma, Epstein Barr virus and PCB levels	National Institutes of Health National Cancer Institute
Infection with Helicobacter pylori and coronary heart disease	Stanford University School of Medicine
Structure and molecular weight of the male sex-specific, cholesterol-like compound in hamster ear sebum	Strang-Cornell Cancer Research Center
Production of cDNA libraries to locate hair-cycle-specific genes	New York University School of Medicine
The relation of previous infection with Chlamydia pneumoniae and/or cytomegalo virus to subsequent heart attacks	Stanford University School of Medicine

Special Project

OFAS is collaborating with Dr. Rigdon Lentz (Tennessee Oncology Cancer Clinic, Nashville), an oncologist with a vision that ultrapheresis (a procedure between dialysis and plasmapheresis) would be a beneficial treatment for malignancies. The concept is that Tumor Necrosis Factor (TNF) is the body's surveillance molecule for destroying cancer cells, but cancer cells make Tumor Necrosis Inhibitor Factor (TNIF) to protect against attacks by TNF. Since this cancer-produced TNIF gets into the bloodstream, washing it out of the blood by ultrapheresis frees TNF to attack the cancer cells. Dr. Lentz pioneered this method using filters specially engineered to selectively remove TNIF. Almost 100 human beings have already been treated by ultrapheresis. OFAS is collaborating with Dr. Gerald Post at the Animal Medical Center (New York, NY), to bring this treatment to animals suffering from cancers that have been unresponsive to surgery, chemotherapy, and/or radiation. But, like any effective treatment, there can be side effects; for example, in this instance, if the tumor is very large, its sudden dissolution can be toxic. Experience may show that primary use of ultrapheresis for early-stage cancer can produce remissions with minimal toxicity and also avoid the need for other therapies.

Studies in Progress

Aging Methionine-restricted diets to increase median and maximum lifespans effects of time of diet's initiation and gender effects of minimal- to zero-methionine diets started later in life mechanism for markedly reduced kidney disease on this diet effect of choice of non-essential amino acid used to substitute for the 'essential' amino acid, methionine

Autoimmune Skin Diseases Alopecia areata and vitiligo identifying and isolating alopecia areata-related antigens testing for presence of hair-related auto-antibodies in human serum developing a mouse model for this human disease, possibly relevant to malignant melanoma characterizing the mouse model for human vitiligo in a photographic log (effects of time, plucking, shaving and breeding)

Hair Evaluation of a new 5alpha-reductase Type I isozyme inhibitor reduction of hair growth in the long-haired Syrian hamster, the OFAS model for human hirsutism reduction of hairloss in the OFAS balding mouse model for human androgenetic alopecia

Metabolism of testosterone by skin difference between strains of mice that do or do not exhibit androgenetic alopecia effect of androgen administration on enzyme activity

Major histochemical and immunohistological changes that occur in androgenetic alopecia

Enzyme activities in resting and growing hair follicles 5alpha-reductase 17beta-hydroxysteroid dehydrogenase 3alpha-hydroxysteroid dehydrogenase

Effect of growth factors (IGF-1, IGF-2 and FGF-2) on human hair follicle performance

Osteoporosis Dentition of the aging jaw