Biochemical Pharmacology, Vol. 57, pp. 329–346, 1999. ISSN 0006-2952/99/$–see front matter © 1999 Elsevier Science Inc. All rights reserved. PII S0006-2952(98)00246-9 COMMENTARY The Importance of Being Dehydroepiandrosterone Sulfate (in the Blood of Primates) A LONGER AND HEALTHIER LIFE? Eugene Roberts* DEPARTMENT OF NEUROBIOCHEMISTRY,BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE, DUARTE, CA 91010, U.S.A. ABSTRACT. The general aging sequence in tissues of healthy human beings is proposed to be: capillary endothelial cell damage 3 arteriosclerosis 3 decreased blood flow 3 metabolic dysregulation 3 secondary a tissue damage. Molecular O2 is an obligatory substrate for the successive syntheses of 17 -OH pregnenolone and dehydroepiandrosterone (DHEA) by cytochrome P450c17 in the zona reticularis of the adrenal cortex, in which 3 3 3 it is suggested that arteriosclerosis decreased blood flow O2 and glucose deficit decreased O2-requiring synthesis of DHEA 3 eventual decrease in number of DHEA-synthesizing cells. Aging changes in the zona reticularis synergize with those in the hypothalamo-hypophyseal machinery that controls it neurally and hormonally, with ACTH-evoked pulsatile floods of cortisol coming from the adrenal zona fasciculata, with the onslaught of free radicals generated by the metabolism of catecholamines released from interdigitating cells of the adrenal medulla, and with age-correlated disabilities of erythrocytes to bind and release O2 to decrease the viability of the DHEA and dehydroepiandrosterone sulfate (DHEAS)-forming cells. One of the chief functions of serum DHEAS in the male may be to act as an allosteric facilitator of the binding of testosterone (T) to serum albumin, thereby helping target T to specific receptors and to allosteric sites for rapid and efficient action at the cellular level. There is reason to consider combining O2 therapy with appropriate administration of DHEA and T to optimize steroid functionality in the healthy aging male, and thus, possibly, to alleviate some of the age-related cognitive and physical decrements that occur. BIOCHEM PHARMACOL 57;4:329–346, 1999. © 1999 Elsevier Science Inc. KEY WORDS. aging; serum steroids; testosterone transport; dehydroepiandrosterone sulfate; arteriosclerosis; endothelial cells; adrenal cortical oxygenation BEYOND MEASUREMENT: THE PATTERN IS cumstances, the survival of individuals and species may THE THING have depended upon the recognition of similarities of Many years ago, a newly trained pediatrician whom I knew patterns and on the discernment of small differences among became utterly distressed upon failing to diagnose his own similar patterns. We know intuitively what pattern recog- child’s illness, which was characterized by a sore throat, a nition is and recognize it by the relief of anxiety or joy high fever, and general malaise. Upon seeing the child, his when we, personally, experience its occurrence. We also mother, whose medical education consisted of raising six can recognize superior pattern-recognizing abilities in oth- children, laughed and said immediately, “Well, of course, ers, whatever the nature of their activities. the child has measles.” The next morning her diagnosis was All living systems are pattern-recognizing or -generaliz- confirmed when the telltale rash appeared. We have ing entities, from single cells to complex human organiza- internalized models, often difficult or even impossible to tions. When a living system, unicellular or international, is express verbally, to which we constantly are matching presented with a new informational pattern in its environ- environmental patterns that arise from our sensory percep- ment (external and/or internal), it is activated in a unique tions. fashion. The types of impinging influences and their se- As in everyday life, so in science, ultimately we search for quences, intensities, and rates of change result in an patterns. We are pattern-seeking and pattern-recognizing activation pattern that is likely to be different, at least to creatures. What begins as single-minded attention to one or some extent, from any experienced previously. Even in a small number of variables often leads to questions of how apparently well-controlled experiments in which single the results might relate to the whole living unit, whether it variables are manipulated, it is the resulting change in the be cell, tissue, organism, or society. Under primitive cir- pattern of the whole environment in space-time that is the stimulus (stress, pressure, forcing function) for the system. When healthy living systems are stimulated effectively, * Correspondence. Tel. (626) 301-8476; FAX (626) 357-1929. processes are released to operate at rates and for durations 330 E. Roberts that enable them to react adaptively in a manner compat- the early normal adult period, degenerative changes are ible with their individual behavioral repertoires. Cascades taking place to some extent, but largely are being compen- of processes are generated by actions of environmental sated for by activities of redundant elements and by factors that reduce transmembrane potential and/or inter- adjustments in feedback and modulator systems. However, act with specific membrane receptors. Cascades of other eventually pathological changes become sufficiently exten- processes are released by expression of genetic potential. sive and repair mechanisms sufficiently attenuated so that When environmental pressures are increased, the number the social behavior and physiological responses of individ- of such countercurrent cascades and their rates and extents uals become maladaptive, and survival becomes dependent are increased in such a manner that the probability of their upon the extensive use of artificial, social and medical meshing to give system-typical adaptive patterns tends to support systems until death ensues. remain approximately constant. The remarkable tendency It is difficult to view problems of human aging at all to maintain relative constancies of structural, composi- levels, from molecular-genetic to social. The loci of com- tional, and functional features of fluids, cells, tissues, and mand-control within the different levels must be identified organs under various environmental conditions (homeosta- and the nature of their hierarchical nesting elucidated. I sis) is indicative of the existence of biochemical and spent several years searching for “threads” from which to biophysical servomechanisms that coordinate a variety of weave some sort of meaningful tapestry into which would complex biosynthetic and degradative pathways and that fit many of the still unconnected observations. Eventually, continuously adjust the rates of flow of substances between it was most useful for me to begin to locate my “threads” by an organism and its environment, between extracellular perusing repeatedly descriptions of the clinical progression and intracellular compartments of tissues, and between of disabilities associated with aging of the human male. cytosol and organelles and among cytosolic aggregates They seemed to read like expansions of Shakespeare’s (molecular ensembles) of individual cells. When it is concise characterization of what happens to a man from the desired to improve suboptimal biological function or to sixth of his seven ages on to his final demise (from As you accelerate repair of damage as a result of disease, injury, or Like It): aging, it is necessary to facilitate adaptive coupling among . The sixth age shifts relevant functional processes by relieving rate-limiting Into the lean and slippered pantaloon, constrictions in mutually shaping interactions among intra- With spectacles on nose and pouch on side, cellular, intercellular, and extracellular components of the His youthful hose well saved, a world too wide system. For his shrunk shank; and his big manly voice, It is difficult to view living systems at all pertinent levels Turning again toward childish treble, pipes because, as Picasso said, “There are so many realities that in And whistles in his sound. Last scene of all, trying to encompass them all ends in darkness. That is why, That ends this strange eventful history, when one paints a portrait, one must stop somewhere, in a Is second childishness, and mere oblivion, sort of caricature. Otherwise, there would be nothing left in Sans teeth, sans eyes, sans taste, sans everything. the end.” The present impressionistic paper is written in the spirit of Einstein’s words “Man seeks to form for himself, in Shakespeare, unparalleled genius of an observer that he whatever manner suitable to him, a simplified and lucid was, had seen clearly that in aging males a loss of muscle image of the world, and so to overcome the world of mass and other, now known to be androgen-related, char- experience by trying to replace it to some extent by this acteristics usually were precedent to obvious mental dete- image.” rioration and death. A somewhat similar script might have been written for female aging and estrogen-related charac- teristics. SHAKESPEARE—AGING AND BLOOD SERUM For as long as they have been known, androgenic and LEVELS OF STEROIDS estrogenic substances have been administered to human An organism does not collapse suddenly of old age like the males and females, respectively, to retard one or another “one-hoss shay.” It does not go “to pieces all at once, — feature of aging. Problems often arose that precluded prolonged use of the hormones. Endometrial bleeding, All at once, and nothing first, — prostatic hypertrophy,