The endocrinological dimensionof ageingAdam S. Wilkins

Contemporary research on ageing and senescence tends to

cluster in three domains. One focus is genes and genetic

theories of ageing, work that is most closely associated with

the ideas of George Williams, Thomas Kirkwood and Michael

Rose. A second deals primarily with ageing effects on cells;

currently, there is much emphasis on oxidative effects in

ageing. A third group of studies is centred on body physiology

and the nature of increasing organ dysfunction during ageing;

this work deals primarily with mammalian systems and

emphasizes, in particular, the nature and kinds of endocrine

dysfunction that take place during ageing. From January 30±

February 1st, a Novartis Symposium convened in London to

consider recent ideas and discoveries in this last area. Its title

was ``Endocrine facets of ageing in the human and experi-

mental animal.'' What follows is a brief account of some of the

highlights.

The introductory remarks were given by the chairman,

J. D. Veldhuis (University of Virginia). He pointed out that

the field needed to identify both the common features of ageing

in different endocrine systems as well as differences between

those systems (``axes''). He also noted the importance of

identifying how and where the so called somatotrophic and

gonadotrophic endocrine systems, often treated as comple-

tely distinct in different studies, intersect.

In several of the following talks, the speakers stressed the

importance of discriminating between the normal changes in

endocrine function that accompany ageing and the distinctly

pathological conditions that can develop. In the first talk,

A.vandenBeld (University Hospital, Rotterdam) discussed

the former. She described a study carried out by her and her

colleagues on ``healthy ageing'' in elderly men. The work

identified gradual losses in muscle tone and in bone mineral

density (BMD) in such men with ageing, the latter partially

correctable by treatment with low testosterone. None of the

hormone therapies, including the much-touted DHEA, how-

ever, can be regarded as a panacea for any of the ageing

defects detected.

Two talks dealt with the relationship between stress and

ageing syndromes and the relationship of both processes to

the functioning of the HPA (hypothalamo-pituitary-adrenal)

axis. B.J. Carroll (Pacific Behavioral Research Foundation,

Carmel) discussed recent findings that have disproved the

long held belief that ageing is accompanied by a pronounced

loss of brain cells with time. Although up to 10% of brain mass

can be lost by the time an individual reaches very old age, this

loss is mostly of white matter (myelin), not grey matter (cells).

What is lost in ageing, apparently, is synaptic connections, not

cells. In addition, the HPA axis can become ``set'' at the wrong

values. This new condition corresponds to an altered equili-

brium and has been termed ``allostasis.'' Intriguingly, allostatic

settings during ageing resemble, in many biochemical, cellular

and cognitive parameters, those produced by high stress.

P. Bjorntorp (University of Goteburg) described how the

HPA axis becomes deranged with respect to cortisol secretion

during prolonged stress. There is a loss of normal feedback,

which becomes more pronounced the longer the stress period.

As in normal ageing, prolonged stress leads to alterations in

the both the gonadotrophic and somatotrophic axes, produ-

cing a complex metabolic syndrome. In women, these alter-

ations are reflected in increased testosterone levels and

increased insulin resistance, the latter associated with a

heightened risk of diabetes.

A number of the talks focussed specifically on ageing

effects on the gonadotrophic axis, in both humans and

experimental animals. Testosterone (T) declines in ageing

men have been linked in the past to reduced muscle mass,

possible cognitive decline, a rise in LDL cholesterol, and

reduced libido and potency. D.J. Handelsman (University

of Sydney) reported on studies on reproductive functions

specifically in ageing men. The results indicate that increasing

sexual dysfunction is related primarily to vasculogenic defects

rather than androgenic deficiency. As in the study by van den

Beld mentioned above, androgen therapy was found not to be

highly effective in reversing ageing-related problems.

C. Wang (UCLA Medical School) reported on work on the

Brown Norway rat, which is a good model system for human

male reproductive ageing. Brown Norway males exhibit

increasing Leydig cell dysfunction and consequent lowered

amounts of T, as occurs in humans. Wang's results indicate

that elevated (induced) nitric oxide synthesis (NOS) levels in

the brain trigger higher levels of apoptosis in the hypothala-

BioEssays 23:555±556, ß 2001 John Wiley & Sons, Inc. BioEssays 23.6 555

The proceedings will be published under the title Endocrine Facets of

Ageing (John Wiley & Sons, Chichester) in October or November of

this year.

Adam S. Wilkins is at the BioEssays Editorial Office, 10/11 Tredgold

Lane, Napier St., Cambridge CB1 1HN, UK.

E-mail: awilkins@bioessays.demon.co.uk

Meetings

mus, leading to diminished HPA signalling (via gonadotrophic

releasing hormone, GnRH) and consequent diminished T

production. Since T feeds back on GnRH production, the

normal oscillatory loop is disrupted. J. D. Veldhuis

described studies in ageing men, which show similar disrup-

tions of the gonadotrophic axis and the feeback loop between

T and GnRH.

The ageing female reproductive axis received comparable

attention in several talks. H. G. Burger (Monash Medical

Centre) described changes in the HPA axis and the ovaries

during the final decade of reproductive life and in the early

years of the menopause. The ovarian follicles contribute two

major components that feedback on the HPA axis, inhibin A

and inhibin B. A sharp decline in follicle stimulating hormone

(FSH), which is normally regulated by inhibin B, is the first,

unambiguous marker of the onset of menopause. J. Prior

(University of British Columbia) reported on her studies of

changes in the period prior to onset of menopause, the

``perimenopause.'' She also finds a decline in inhibins and in

progesterone during the perimenopausal period. A second

physiological change associated with the onset of menopause

is a decrease in BMD, which is found in all studies. Prior's

studies indicate that it begins before marked declines in

estradiol while other analyses, described by B.L. Riggs

(Mayo Clinic) indicate that such declines are a major causal

factor. Although this difference of opinion was not resolved at

the meeting, it seems generally agreed that changes in sex

steroids are a major factor in loss of BMD. Spriggs described

the proximate trigger of bone loss as involving altered calcium

homeostasis as a consequence of increased parathyroid

hormone (PTH) production.

Other talks focussed on alterations in the somatotrophic

axis in ageing and in other conditions. Z. Laron (Tel Aviv

University), the co-proposer of the meeting (along with

Veldhuis), described some paradoxical effects of multiple

pituitary hormone deficiency (MPHD) in humans. These

individuals are deficient in both IGF1 and GH and show

various signs of premature ageing though, oddly, they exhibit

less greying of hair with age. The striking finding from several

communities where this condition exists at elevated fre-

quency, however, is that there is no sign that it is correlated

with shorter life span. Indeed, animal models for this condition,

the Ames and Snell dwarf mice, as well as the GH receptor

knock out mouse (Laron mouse), live longer than normal mice.

Laron, who pioneered the use of GH therapy in GH-deficient

children, pointed out that there is evidence that excess GH

actually shortens life-span. On the other hand, GH-deficient

individuals are more subject to osteoporosis and cognitive

defects. Clearly, there is an optimal range of GH concentra-

tions and the optimum is probably a function of age.

In normal individuals, GH levels decline during ageing. This

decline is correlated with a decline in IGF1 and an increase in

insulin, as reported by A. Ruiz-Torres (Universidad Auton-

oma de Madrid). These changes affect the cell biology of

human vascular smooth muscle cells, leading to atherogen-

esis. Georg Brabant (Medizinische Hochschule Hannover)

reported data on the hypothalamo-pituitary-thyroid axis. The

findings indicate relatively little alteration in this axis with

ageing and when such does occur, it is usually secondary to

nutritional deficits in the elderly. In effect, this is one part of the

somatotrophic axis that does not seem to be too seriously

affected by ageing. D. Elahi (Massachusetts General

Hospital) described the phenomenon of increasing insulin

resistance during ageing, a frequent precursor state to

diabetes. Insulin resistance reflects, in part, decreased

sensitivity of the pancreas beta cells to the insulinotropic gut

hormones (GLP and GIP) which are produced by the gut in

response to eating. S.M. Shalet (Christie Hospital NHS

Trust, Manchester), speaking for a Belgian investigator who

could not attend, described studies on individuals with

prolonged critical illness. The data indicate that the patholo-

gies associated with these states bear only a slight resem-

blance to normal ageing processes although there may be

some effects on the hypothalamus and consequent effects on

the gonadotrophic axis. Finally, D. Robertson (Vanderbilt

University) described some age-related effects on the

autonomic nervous system and the surprising fact that drinking

16 oz of tap water restores blood pressure with concomitant

relief of some of the autonomic system defects. (This will

surely be one therapy not subject to intense commercial

exploitation!)

The Symposium was a highly interesting, stimulating and

enjoyable one, with lively participation by all and the present-

ation of much new material. As the findings reported at this

meeting come to be synthesized with the two other major

bodies of senescence research, those on the genetics and cell

biology of senescence, one can anticipate still more informa-

tive and exciting developments in ageing research to come.

Meetings

556 BioEssays 23.6