First International Congress of Biomedical Gerontology

Neurobtolog* of Aging, Vol 6 pp 249-251. 1985 e Ankho Internatmnal lnc Pnnted m the U S A

0197-4580/84 $3 00 + 00

MEETING REPORT

First International Congress of Biomedical Gerontology MICHAEL

J PONTECORVO

NOVA Pharmaceutwals, 5210 Eastern Avenue, Balttmore, MD 21224-2788 AND REGINALD

L DEAN

Medwal Research Dtwston o f Amerwan Cyanamtd Company Lederle Laboratorws, Pearl Rtver, N Y 10965 these papers that considerable controversy stdl exists concernmg the potential of these compounds to lengthen maximal life span and increase neuronal function Indeed, R G Cutler (USA) suggested that on the basis of cross species comparisons, levels of some endogeneous anti-oxidants msght actually be negatwely correlated with hfespan and hence that the abdlty to protect agamst damage from free radicals m~ght have no necessary correlation wsth Iongevsty Still then, dtscusslons centered on the dzfficultles m demonstratmg that changes m free radical levels were actually responsible for (not just correlated with) certain age related disturbances (e g , changes m membrane permeabshty) Thus, it was clear that further research is necessary to apprecmte the role of free radicals m the aging process

T H E First Internatmnal Congress of Bmmed,cal Gerontology, sponsored by the American Aging Assocmuon, was held on July 10-11, 1985 m New York City The purpose of th~s Congress was to ( ! ) make the general pubhc more aware of the potentml of b,omed~cal aging research and to increase the span of healthy productive life and to decrease the social and economic problems o f age, (2) promote greater commumcatlon between international scientists engaged m biomedical aging research, and (3) formally orgamze the International Assocmtlon of Bmmedlcal Gerontology, involving individuals and national organizations concerned w~th biomedical aging research The meeting was eclectic m nature w~th presentatmns covermg a broad range of research topics As such, only those areas involving the neuroblology of aging will be reported here F o r those interested, the abstracts will be pubhshed in the July 1985 zssue of Age, the journal of the A m e n can Aging Assocmtmn

CLINICAL TREATMENT AND DIAGNOSIS A second group of papers discussed issues related to the diagnosis and treatment of disease m the elderly R T Bartus (USA) pointed out that the elderly c o m p n s e a disproportionately large segment of the market for a wide number of therapeutic drugs, yet most compounds are not developed nor tested chmcally w,th the special needs of the elderly m mind Bartus cited wide variations m effective dose, exacerbated side effects and complications due to multiple drug use and chronic admm,stration as cons~deratmns m designing and prescnbmg drugs for the elderly Pharmacokmetlc differences may also exist, as was noted by both Bartus and C F A Van Bezoouen (The Netherlands), who reported age related changes m cytochrome P-450 lsoenzymes that may make it difficult to predict the m vtro clearance of hpophlhc drugs Difficulties m designing effective pharmaceutical therapies may also be exacerbated by dsfficulties in dmgnosls among the elderly and by the presence of heterogeneous subpopulatlons Three papers addressed these issues S S Matsuyama (USA) reported that men with a chmcal diagnosis of early onset Alzhelmer's disease (AD) were more likely (10/10 subjects) than men with late onset A D or women with AD (40 a4%) to show A2 type human leukocyte antigens These data are consistent w~th other recent data

FREE RADICALS An important theme of the conference was the role of free radicals m the aging process Free radicals are an intermedlary by-product m a number o f metabolic pathways Since free radicals are highly charged and because the concentration of free radicals increases with age, it was suggested that they may account for a range o f age related functional disturbances F o r example, H Nohl (Austria) reported that free radicals can brad to mitochondrlal membranes reducing flmdity and overall energy productmn Similarly, I Zs-Nagy (Hungary) attributed the age related mcrease m cell membrane permeablhty to the effects o f free radicals Finally, S J Stohs (USA) reported that age related changes m liver hpid peroxldatlon and D N A damage were reversely correlated with tissue levels ofglutathmne and that the age related DNA damage could be partmlly reduced by administration o f ant~-ox~dants such as altnpaz A number of other studies reported by I Semsel (Hungary), J Remacle (Belgmm), S P Sharma (India) and V V Frolkls (USSR) also addressed the possible protecUve effects o f anti-oxidant agents However, it was evident from the dlscussmn of all of

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suggesting that differences may exist between patients with early and late onset AD However, the slgnaqcance of M a t u s y a m a ' s findings remains unclear since aged, but cognmvely unimpaired subJects also show a slgmficant incidence (3~c) of the A2 antigen Slmdarly, B Glerl (USA) reported that patients with dementia actually, had higher levels of blood cortisol followm g a dexamethasone suppression test (DST) than did nondemented, but depressed patients Although this finding may have implications for the etiology of dementia, Jt also further emphasizes the difficulties in clinically distmgmshlng dementia and depression Finally, M J Redmg (USA) reported a double blind study that showed that stroke patients suffering from post-stroke depression (evidenced by a DST or Zung depression scale) showed improved scores on activmes o f dmly living (ADL) scale when treated with the antidepressant trazadone In contrast, stroke patmnts who revealed no evidence of depression did not benefit from trazadone, and if anything, had lower A D L scores than untreated controls Together these findings emphasize the importance of diagnosis and attention to subtypes and coincidence of disease in the elderly NEURONAL DYSFUNCTION Five papers examined age related neuropathologlcal changes Of particular interest was R G Struble's (USA) report that lmmunoreactlvlty to a number of neuropepttdes Including somatostatm, cholecystoklnln, substance P and vasoactwe intestinal peptide could be detected m neuntes assocmted with senile plaques in the brains o f Aizhelmer's disease patients Moreover, Struble reported that reactivity to a particular type o f neuropeptide tended to be concentrated m neuntes from specific areas of the brains, whereas sende plaques could be found throughout the hippocampus and cortex It remains unclear whether this localization simply reflects the normal distribution of the various neuropeptide producing neurons, or whether some selective risk exists for neuropeptlde-contammg neurons in specific brain areas Further research into these questions might provide greater insight into the etiology of AD and, the involvement of various neurotransm~tter systems m the disease In addltlon to Struble's paper, K lqbal (USA) reported on two methods for isolating paired helical filaments (PHF) from Alzhelmer's disease brains and concluded that the method o f isolation may influence the solublhty of P H F This finding Is Important since lack of solubility has been an important barner to understanding the chemical composition of P H F In addition, T I Mandybur (USA) summarized the results of neuropathologlcal examinations o f brains from 88 patients with AD and 102 normal patients, m an attempt to determine the most frequent patterns of certain morphological cerebral changes (senile plaques, tangles, granulovascular neuronal degeneration, cerebrovascular amyloldosls and L e w y bodies) which might be responsible for manifestations of dementia The results indicate that only patients showing massive sende plaques and tangles always had at least some dementia The combination of.lust senile plaques and cerebrovascular amyioldosls appeared to be least associated with dementia Mandybur concluded that the primary dementogemc process in AD must involve a more basic failure of the cortex, while the lesions represent a secondary change, m which the intensity dose not reflect the degree offadure J E Johnson (USA) reported on the use of aged rat tissue as a

means of distinguishing between normal aging and neuropathology m humans under electromlcroscoplc examination F o r example, in AD brain tissue, Lewy bodies, filament masses, virus-like particles, dense-cored mitochondna, hpofuscm with small dense granules, and membranous arrays were found In aged rat tissue, mltochondna with dense cores, and some o f the membranous arrays were seen, which suggested that these structures were simple age-related changes and were not pathological or artifactual in orgln Johnson concluded that aged rat specimens have great value m distinguishing aging, disease and artifacts m human tissue Finally. K Kuboto (Japan) reported that smoking decreased cerebral blood flow and brain volume in aged humans AGING AND THE CHOLINERGIC SYSTEM I Klsemshsky (USA) reported no significant differences in brain blood flow, 02 extractlon (arterial-venous blood 02 concentration) or total 02 consumption (blood flow x 02 extracted) between 3 and 33 month old rats AF64A (a presynaptic chohnerglc neurotoxln) ln,lected bilaterally into the hlppocampus produced a decrease in brain blood flow for both old and young rats, but decreased 02 extraction only in the young rats The authors suggest that the chohnergic system may have less influence on brain oxygen consumption in old than in young rats Alternatively the AF64A lesions may have had less effect m the old than the young rats P P Rowell (USA) reported on the effect of life long (from 2 to 20 months) dietary supplement with choline and lecithin In contrast to previous reports, there was no beneficial effect of chronic choline or lecithin on brain morphology (l e , there was no increase m the number of dendritic spines on hlppocampal mossy fibers) Moreover, chronic lecithin (but not choline) reduced the number of muscarmic receptors in the hippocampus and cortex These findings suggest that chronic treatment with lecithin enriched diets may actually have negative consequences on certain brain parameters Lecithin administration had been proposed by others to be a better vehicle for increasing choline levels because esterfied choline is absorbed and tolerated by patients better than choline A D Kehr (USA) utilized lmmunohistochemical techniques to examine the long term consequences of unilateral ibotenlc acid lesions o f the nucleus basahs (NBM) Contrary to previous reports with unilateral NBM lesions, Kehr reported a persistent reduction (180 days post-lesion) in the number of CHAT positive neurons in the lesioned NBM, as well as a reduction in the staining for cortical C H A T and A C H E These findings are consistent with the peristent decreases in cortical chohnergic markers previously reported for bilateral NBM lesions Careful parametric studies exammmg the factors that contribute to neurochemical as well as behavioral recovery following NBM lesions might provide insight G Aston-Jones (USA) reported that antidromic conduction l a t e n o e s from cortically stimulated NBM neurons mcreased as a function of age in rodents Furthermore, comparison of latencles elicited from superficial and deep cortical projections suggested that conduction speeds in the cortex were virtually identical in young and aged rats These findings suggest that a subcortical change, possibly involving a loss of myhnatlon of the fiber tracts, may be responsible for the age-related dysfunction If confirmed, th~s finding could have important implications with respect to the chohnergic dJsturances reported m humans with AD

251 Finally. N W Pedlgo (USA) reported an age-related decrease in muscarlnlC receptor plasticity in the frontal cortex of rats Although young rats were able to increase or decrease the number of muscarlnlC receptors in response to chromc treatment with chohnerglc drugs (oxotremorlne or methylatroplne), aged rats showed httle or no compensatory change These findings suggest that tolerance to chromc treatment may not be a problem when administering chohnergic agonlsts to aged, demented humans However, they also suggest some possible dysfunctions in postsynaptlc receptor function that m~ght prevent treatment with chohnerg~c agonlsts from hawng the therapeutic effect

Other topics that received attention but not reviewed were Aging and exercise Interactions on skeletal, muscle tissue and longevity, Aging and ~mmune responses, and Age effects on protein synthesis and composition Finally, the International Association of Biomedical Gerontology was officially formed on July l l, with the Second International Congress scheduled for mid-July, 1987 in Hamburg, West Germany F o r further information concerning meeting and membership information contact The International Association of Biomedical Gerontology, American Aging Association, Attn Denham Harman, M D . Umverslty of Nebraska Medical Center, Omaha, NE 68105 USA