Primary Locus Intervention: A novel approach to treating age-associated hormone insufficiency

There is consensus among practitioners of age-management/longevity medicine that progressive failure of neuroendocrine function leads to hormone insuffi ciency, which underlies many of the maladaptive consequences of aging. Accordingly, one of the most commonly employed clinical interventions in aging is balanced hormone replacement therapy (HRT). This approach is often quite effective since many of the structural and functional consequence of aging result at least in part from inadequate endogenous hormone supply and/or imbalance of multiple hormone actions upon the body. However, while HRT is effective in opposing many of the more obvious degenerative effects of aging on body composition and function it does little to treat the pathophysiologi-cal factors underlying neuroendocrine decline. In fact, HRT may actually accelerate senescence of neuroendocrine elements within the brain and pituitary gland. Growth hormone replacement therapy (GHRT) which has been the cornerstone of age-management HRT for many years provides a familiar example of this paradox. The basis for prescribing recombinant growth hormone (hGH) to sustain health during aging derived from observation of young adults who received hGH as children to treat short stature. Once those children reached their fi nal height, GHRT was discontinued because hGH was thought necessary only to stimulate growth. However, it soon became apparent that growth hormone defi ciency (GHD) in these young adults had signifi cant negative consequences on their health and vitality. Such individuals experienced increased risk for development of life threatening disorders such as high blood pressure, diabetes, cardiovascular disease and cancer. Signifi cant to practitioners of age-management medicine was the fact that these diseases also typically occur in normal adults during middle age and later. Coincidentally, growth hormone production and secretion declines progressively with advancing age, and that such change correlates with increased risk for the same intrinsic diseases observed in GHD young adults. However, it also became apparent in older adults receiving hGH that the hormone had biphasic effects in which overdosing produced many of the same symptoms as defi ciency, eg, hyperglycemia, increased blood pressure, etc. These effects were attributed not only to over dosage, but also to the unnatural, pharmacological presentation of the hormone resulting from bolus administration. Because hGH metabolic dynamics is controlled by a feedback network consisting of stimulatory and inhibitory elements, its normal physiological pattern of release from the pituitary is episodic. In contrast, an injection of hundreds of micrograms and even milligrams of hormone produces a " square wave …