Prolongation of the Life-Span in Mice Adapted to Large Amounts of L-Dopa

Abstract

Various concentrations of L-dopa (levodopa, L-3,4-dihydroxyphenylalanine) were incorporated in the diets of young male Swisg albino mice, and the highest coneentrations to which these mice became adapted within 3 weeks were determined. One such concentration administered indefinitely eventually indticed a youthful appearance, a signifilantly prolonged life-span, but also corneal opaeities compatible with traumatic or chemical keratitis.The use of idopa (L-3,4-dihydroxyphenylalanine, levodopa) in the long-term treatment of Parkinson's disease, a chronic affliction, necessitates initial adaptation to high doses followed by sustained consumption of this amino acid (1, 2). Like other long-term regimens, treatment with t-dopa requires the physician's skill and care and the patient's cooperation, and even so, certain side effects can emerge (3). Shortly after the publication of papers describing the therapeutic effects of L-dopa (1, 2), many kinds of illness in patients with Parkinsonism wete being ascribed by others to idopa as its side effects, whether or not the recommended regimen was followed. The accruing literature, too voluminous even for references here, gave rise to fears about the long-term influence of idopa on patients' general health. These fears have been slow to recede despite (i) subsequent reports that iLdopa is the most effective drug for treating Parkinson's disease (see ref. 4) and (ii) the fact that no deaths of treated patients have been ascribed to idopa, in sharp contrast to findings with all other major drugs.In our investigations on the effects of L dopa on general health, we initiated animal experiments to supplement our long-term observations on human patients. Since life-span can be considered as an indicator of health, we determined the maximal concentrations of -dopa incorporated in the chow to which mice could become adapted so that we could then study the effects of a very high concentration on longevity. The results show that this amino acid could either kill the mice or significantly extend their life-span and apparent prime of life, depending on the way it was given. Some of the longevity data, although preliminary, are being presented here to expedite studies of the relevance of these long-lasting experiments to human patients. MATERIALS AND METHODSAnimals. Most of the animals were 4-5 week-old, male Swiss albino mice of the Hale-Stoner strain. In some experiments females of the same strain and age, and aging males, were also used. Cages containing six mice (or two, in the case of aging males) were kept in air-conditioned rooms with controlled humidity, lighted 12 hr each day.Diets. Ground Purina chow was given freely, plain for the controls and with certain concentrations of idopa (levodopa, i-3,4-dihydroxyphenylalanine, Nutritional Biochem. Corp.) added for the test mice. The Purina chow itself, in contrast to some other rodent diets (5, 6), did not contain a measurable amount of idopa. The different -dopa concentrations in the chow mixtures, as determined spectrofl...

L-3,4-dihydroxyphenylalanine-induced hypersensitivity simulating features of denervation.

“…It must be emphasized, however, that the dopaminergic apparatus innervates several additional cerebral structures (26)(27)(28). Since some of the dietary doses of levodopa tested here had earlier increased the mean life span of mice (16,17), it is probable that the activity of the enzyme located in other structures (28) had also been changed by chronic feeding of levodopa.…”

“…One or more of these groups received levodopa in their Purina Laboratory Chow while one consumed Purina without the drug. The HS mice received the amounts of dietary levodopa that had increased their lifespan (40 mg of drug per g of chow) (16,17). The concentration given to the C3H/HeJ mice (100 mg/g of body weight) was approximating the maximal tolerated one.…”

Dopamine and Aging: Intersecting Facets

“…L-DOPA may accelerate progression via upregulating DA metabolism in a declining cell complement. In normal animals, however, up-regulation of DA or norepinephrine (NE) (peaks correlate with hypothalamic-pituitary-adrenal axis [HPA] activity) can improve longevity, restore growth hormone (GH) pulse amplitude and re-initiate estrous of old rodents [e.g., 68,69].…”

Effect of Treatment with Phenformin, Diphenylhydantoin or <i>L</i>-Dòpa on Life Span and Tumour Incidence in C3H/Sn Mice

“…The ineffectiveness of A-dopa treatment is perhaps due to the dosage used in our experiments (about 6 0 -9 0 mg/kg), because other authors reported an effective inhibition of DMBA-induced mam mary carcinogenesis by A-dopa administration to rats ( Welsch and Nagasawa, 1977). It should be mentioned that prolongation of mouse life span was attained by treatment with much higher doses of A-dopa (5,000 mg/kg), which, however, caused toxic side effects (Cotzias et al, 1974).…”