Evidence that underfeeding acts via the neuroendocrine system to influence aging processes.
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Aging↗
Biomedical subjects
J Meites
Publications and source records attributed to J Meites.
Neuroendocrine biomarkers of aging in the rat.
The genome and environmental agents are believed to regulate aging processes mainly via the homeostatic and integrative mechanisms of the body, which consist primarily of the neuroendocrine, immune and cell-to-cell communicating systems. Of these, the neuroendocrine system is considered to be the most important since it regulates to a greater or lesser degree all body functions, in old age as well as in early and mature life. We have studied mainly three aging events in the rat: the reproductive decline, development of numerous mammary and pituitary tumors and the decrease in GH secretion and protein synthesis. We have found that all three are caused primarily by faults that develop in hypothalamic function, particularly the decline in norepinephrine (NE) and dopamine (DA) activity. This decline appears to be caused largely by damage to hypothalamic neurons as a result of the chronic action of hormones, toxins, free radicals, cross linkages, lipofuscin accumulation and "wear and tear". Administration of drugs that increase hypothalamic NE and DA activity can delay or reverse all three aging events. Changes in hormone secretion, estrous cycles, tumor development and protein synthesis can be measured and used as "biomarkers of aging" in the rat.
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Differential activity of thymosin peptides (thymosin fraction 5) on plasma thyrotropin in female rats of different ages.
Thymosin fraction 5 (TF-5), a partially purified thymic preparation, has been previously shown to have luteinizing-hormone-releasing-hormone-releasing activity in perfused rat hypothalamus as well as an in vivo stimulatory effect on the pituitary-adrenal axis in prepubertal monkeys. We report here the effect of TF-5 on the plasma levels of several hormones in female rats of different ages. Conscious free-moving Sprague-Dawley rats carrying an indwelling atrial cannula received a single dose of 5 mg/kg body weight of either bovine serum albumin (BSA) or TF-5 via cannula. In young (3-4) months and old (25 months) rats, thymosin induced a marked reduction of plasma thyrotropin (TSH) which was significantly greater than the normal circadian decline observed in the BSA-treated controls. Senescent females (34 months) displayed high basal levels of TSH which showed little circadian rhythmicity and did not respond to TF-5. Thyroxine (T4), triiodothyronine (T3), corticosterone, and prolactin levels were not affected by TF-5 at the dose levels tested. An age-dependent decrease in basal plasma levels of T4 but not T3 was observed in both BSA- and TF-5-treated rats. Young females given up to 10 mg BSA/kg body weight (i.v.) and noninjected controls had similar levels of the above hormones up to 3.5 h after BSA injection. These results suggest that the thymus has an inhibitory action on TSH in the rat, which is not mediated by the thyroid gland. Our results also suggest an age-related desensitization of the TSH system to thymic influence in this species.
Aging↗
Immune-neuroendocrine interactions during aging: age-dependent thyrotropin-inhibiting activity of thymosin peptides.
Thymosin fraction 5 (TF-5), a partially purified thymic preparation, has been previously shown to have luteinizing hormone-releasing hormone (LH-RH)-releasing activity in perfused rat hypothalamus as well as in vivo stimulatory effect on the pituitary-adrenal axis in prepubertal monkeys. We report here the effect of TF-5 on the TSH-thyroid axis in young (3 months) and old (25 months) Sprague-Dawley male rats. Conscious free-moving animals carrying an indwelling atrial cannula received a single dose of 5 mg/kg body wt. of either bovine serum albumin (BSA) or TF-5 via the cannula. In the young rats, TF-5 induced a marked reduction of plasma thyrotropin (TSH) which was significantly greater than the normal circadian decline observed in the BSA-treated controls. The old males displayed high basal levels of TSH which showed no circadian rhythmicity, and did not respond to TF-5. Thyroxine (T4), triiodothyronine (T3), corticosterone, and prolactin levels were not affected by TF-5 at the dose levels tested. The old rats had significantly lower basal levels of T4, but not T3, than their young counterparts. The synthetic peptides thymosin alpha-1 and serum thymic factor, which are components of TF-5, had no effect on the above hormones when injected in doses up to 5 micrograms/kg body wt. Acute thymectomy in 3-month-old males induced a significant increase in basal levels of TSH without affecting plasma T4 or T3. These results suggest that the thymus has an inhibitory action on TSH in the rat, which is not mediated by the thyroid gland.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Why the neuroendocrine system is important in aging processes.
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Aging↗
Half-life of plasma growth hormone in young and old conscious female rats.
The kinetics of disappearance of plasma GH was studied in young (3-4 months) and old (24-27 months) Sprague-Dawley female rats. Conscious, free moving animals carrying indwelling atrial and carotid cannulas received a single injection of 125I-rGH via the carotid cannula. Sequential blood samples were removed at intervals during the following hour, and total (TR) and immunoprecipitable radioactivity (IPR) were determined in the corresponding plasmas. Both TR and IPR displayed biexponential kinetics in vivo which did not differ significantly, for each variable, between young and old animals. The volumes of distribution of GH were also similar in both age-groups. The IPR/TR ratio, an estimate of GH inactivation within the plasma space, showed a decreasing sigmoid-shaped kinetics in vivo with a time of semi-inactivation (ti1/2) of 23.8 +/- 1.2 and 29.0 +/- 1.0 min (mean +/- SE) for young and old rats, respectively (P less than 0.02). The estrous status did not significantly affect ti1/2 values in vivo. The in vitro t1/2 was estimated by incubating plasma from the young and old animals at 37 degrees C with 125I-rGH for several hours. The IPR/TR ratio displayed a linear kinetics in vitro with t1/2 values of 23.7 +/- 1.7 and 25.8 +/- 1.9 h (NS) for young and old animals, respectively. The above results show that GH catabolism decreases slightly with age in the female rat, although it is unlikely that this change has a significant effect on plasma levels of GH. The data also suggest that GH is physiologically inactivated in the extravascular space.
Aging↗
Growth hormone secretory patterns in young, middle-aged and old female rats.
Pulsatile growth hormone (GH) secretion was compared in young (5 months), middle-aged (11 months) and old (25-29 months) female Sprague-Dawley rats under nonanesthetized, free-moving conditions. Mean plasma GH levels were 99.1 +/- 9.3 ng/ml in young rats, 56.3 +/- 5.8 ng/ml in middle-aged rats and 49.7 +/- 4.9 ng/ml in old rats (p less than 0.01 for young vs. middle-aged and old rats). In young females, 10 out of 17 rats had GH pulses with peak levels greater than 200 ng/ml, in 6 middle-aged females all GH peaks were below 200 ng/ml, and in old females 13 out of 17 rats showed GH peaks of less than 100 ng/ml. The average peak (amplitude) of GH pulses in the old rats (69.3 +/- 8.3 ng/ml) was lower than in the young rats (130.4 +/- 17.5 ng/ml, p less than 0.01) and somewhat lower than in the middle-aged rats (87.0 +/- 8.9 ng/ml). There was no change in intervals between GH pulses. Pituitary GH content in middle-aged and old females (1,189 +/- 60 and 1,100 +/- 89 micrograms, respectively) was significantly lower (p less than 0.05 and p less than 0.01, respectively) than in young female rats (1,464 +/- 76 micrograms). Somatostatin content in the median eminence of old rats (22.4 +/- 1.9 ng) was significantly lower than in young rats (28.5 +/- 1.6 ng, p less than 0.05). It is concluded that GH secretion is reduced in aging female rats, but unlike in aging male rats the decrease is seen at an earlier age.(ABSTRACT TRUNCATED AT 250 WORDS)
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Bromocryptine prevents the decline in tuberoinfundibular neuronal release of dopamine after removal of chronic estrogen treatment.
Prolonged exposure to estradiol 17-beta (E2) in rats has been shown to decrease dopamine (DA) synthesis in and release from tuberoinfundibular dopaminergic (TIDA) neurons in Fischer 344 rats. The objective of the present study was to determine whether inhibition of the E2-induced increase in anterior pituitary (AP) weight and prolactin (PRL) secretion by concomitant administration of the dopaminergic agonist, bromocryptine, could prevent the decrease in TIDA neuronal function produced by chronic E2 administration. TIDA neuronal function was evaluated by in vitro superfusion and electrical stimulation of median eminence (ME) tissue after allowing for accumulation of [3H]dopamine (DA). The effect of chronic E2 and/or bromocryptine treatment on catecholamine content in tuberohypophyseal neurons in the neurointermediate lobe was also measured to determine whether increased pituitary size possibly damaged the tuberohypophyseal neurons. Treatment with E2 for 30 days significantly increased AP weight, serum PRL concentration, and AP PRL and DNA content over values in non-E2-treated controls. When bromocryptine was injected daily during E2 treatment, bromocryptine completely inhibited the E2-induced increase in serum PRL and AP DNA content, and AP weight was only moderately increased. The evoked release of 3H at the end of the 30-day E2 treatment was reduced during electrical stimulation and there was no augmented release of 3H from the ME tissue after 10 microM nomifensine infusion in E2-treated rats and in rats given both bromocryptine and E2. However, neurointermediate lobe DA content was diminished only in E2-treated rats and not in animals given bromocryptine together with E2. When all treatments were discontinued for 30 days, animals previously given only E2 showed sustained increases in AP weight, serum PRL levels, and AP PRL and DNA content, but reduced stimulation-evoked release of 3H, absence of response to nomifensine, and reduced neurointermediate lobe DA and norepinephrine content when compared with values in non-E2-treated controls. After withdrawal of E2 treatment for 30 days, animals previously given bromocryptine and E2 together were not different from control animals in any of the parameters measured. These results suggest that the decline in TIDA neuronal release of DA induced by chronic E2 treatment was at least partly exerted via the marked hyperprolactinemia and/or by compression of the medial basal hypothalamus by the enlarged AP.
Animals↗
GH binding to liver in young and old female rats: relation to somatomedin-C secretion.
Age-related changes in binding of 125I-bovine GH to liver membrane fractions were measured in female Long-Evans rats 2, 6, 12 and 20 months of age. Specific GH binding did not change between 2 and 6 months of age but increased significantly at 12 and 20 months of age. Scatchard analysis showed that the plots were curvilinear and consisted of high- and low-affinity binding sites. The age-related increases in binding sites were mainly due to an increase in number of low-affinity binding sites. Serum somatomedin-C (SM-C) levels in 20-month-old rats were about half those in the 6-month-old rats. Twice daily injections of ovine GH (2 mg/kg body wt) for 7 days depressed liver GH binding and increased serum SM-C levels in 19-month-old female rats, but had no effect on GH binding in 2-month-old female rats. These results suggest that the increase in liver GH binding sites and the decrease in SM-C secretion are associated with our previously reported decrease in GH secretion in old female rats.
Aging↗
Importance of the neuroendocrine system in aging processes.
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Aging↗
Degradation of immunoreactive albumin in young and old conscious female rats.
The kinetics of inactivation of plasma albumin was studied in young (3-4 months) and old (25-28 months) Sprague-Dawley female rats. Conscious, free-moving animals carrying indwelling atrial and carotid cannulas received a single injection of [125I]-albumin (rat) via the carotid cannula. Sequential blood samples were removed at intervals during the following 120 min, and total (TR) and immunoprecipitable radioactivity (IPR) were determined in the corresponding plasmas. TR disappearance curves for young and old animals were almost identical but IPR disappearance curves showed a significantly faster decline in the young rats. The absolute plasma volumes for young and old rats were (mean +/- S.E.M.), 10.8 +/- 1.1 and 14.4 +/- 1.5 ml, respectively (P less than 0.05). The IPR/TR ratio, an estimate of albumin inactivation within the plasma space, showed a monoexponential decrease in vivo with a t 1/2 of 11.4 +/- 5.1 and 39.3 +/- 10.8 h (P less than 0.05) for young and old rats, respectively. The in vitro t 1/2s for albumin were 5.25 +/- 1.02 and 3.42 +/- 0.91 days (NS) for young and old rats, respectively. It is concluded that: the rate of albumin catabolism declines with age in the female rat; albumin is mainly inactivated in the extravascular space; and total plasma volume increases significantly with age in this species.
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Increased secretion of somatostatin-28 from hypothalamic neurons of aged rats in vitro.
The purpose of this experiment was to determine whether increased secretion of somatostatin or alterations in its molecular form contribute to the age-related decline in growth hormone secretion. Median eminences were removed from male Sprague-Dawley rats (3-4 and 21-24 months of age) and superfused with Krebs-Ringer bicarbonate buffer with 0.5 mg/ml bacitracin. After 40 min, tissues were stimulated with 55 mM K+ for 5 min and fractions collected for 60 min. Tissue and superfusate were analyzed for somatostatin using a highly specific antiserum which cross-reacts with somatostatin-14 and -28. Somatostatin release was expressed as a fractional efflux of somatostatin tissue content. In young rats, somatostatin increased from basal levels of 22 +/- 5 X 10(-4) to 57 +/- 3 X 10(-4) in response to 55 mM K+ and returned to basal levels. Old rats exhibited similar basal levels of somatostatin efflux (25 +/- 5 X 10(-4)) but increased to 91 +/- 19 X 10(-4) in response to K+. This represents an 89% greater increase in somatostatin fractional efflux in old as compared to young rats (P less than 0.05). The molecular form of somatostatin released during K+ stimulation was determined by fractionating samples on Sephadex G-25. In young animals, both somatostatin-14 (31% of total immunoreactivity) and somatostatin-28 (69% of total immunoreactivity) were released by hypothalamic neurons. In old rats, similar absolute levels of somatostatin were released in response to K+ but greater quantities of somatostatin-28 (87% of total immunoreactivity) were secreted.(ABSTRACT TRUNCATED AT 250 WORDS)
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Effect of CNS-active drugs on TRH-induced prolactin release.
The effects of several central acting drugs upon thyrotropin-releasing hormone (TRH)-induced increases in prolactin (PRL) release were compared in estrogen-primed male rats. Administration of the serotonin antagonist, p-chlorophenylalanine, or the opiate antagonist, naltrexone, did not alter TRH-induced release of PRL. Pre-treatment with either the dopamine agonist, piribedil, or the cholinergic agonist, pilocarpine, resulted in significantly reduced TRH-induced PRL release. Pilocarpine did not inhibit the TRH-induced increase in PRL release when rats were first pre-treated with the dopamine receptor blocker, haloperidol. These results indicate that the dopaminergic and cholinergic systems can modify TRH-induced release of PRL in vivo.
Animals↗
Evidence for a permanent decline in tuberoinfundibular dopaminergic neuronal function after chronic estrogen treatment is terminated in Fischer 344 rats.
Long-term 17 beta-estradiol (E2) treatment in rats decreases tuberoinfundibular dopaminergic (TIDA) neuronal function. The objective of this study was to determine if the decline in TIDA function after E2 treatment in Fischer 344 (F344) rats is sustained long after removal of E2. Ovariectomized (OVX) F344 rats were each implanted with an E2-containing or empty Silastic capsule for 4 weeks; the capsule was then removed, and 26 weeks later acute experiments were performed. Release of 3H from median eminence tissue in vitro in response to electrical stimulation after 3H-DA accumulation was not different between E2-treated rats and OVX controls, even though serum prolactin (PRL) was 4-fold greater in E2-treated animals. Acute administration of apomorphine hydrochloride, a DA receptor agonist, at 2 doses, reduced serum PRL values as much in E2-treated animals as in OVX control rats. Injection of morphine sulfate or nomifensine maleate, which directly influence TIDA neurons, resulted in nonsignificant serum PRL responses in animals long after E2 withdrawal as compared to the greater response in OVX control rats. To further evaluate TIDA neuronal function, OVX non-E2-treated rats and animals 26 weeks after E2 withdrawal received a 3-day E2 challenge which increased the stimulation-evoked release of 3H from the median eminence tissue in vitro 2-fold in OVX control rats but had no effect in rats given E2 26 weeks previously. The difference in the stimulation-evoked release occurred in the presence of similar circulating serum PRL levels in the two groups as a result of the 3-day E2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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Persistence of low hypothalamic dopaminergic activity after removal of chronic estrogen treatment.
The purpose of this study was to determine whether inhibition of tuberoinfundibular dopaminergic (TIDA) neuron function which occurs during chronic estrogen administration persists after removal of the estrogen. Ovariectomized (OVX) Fischer 344 (F344) rats were implanted for 4 weeks with a Silastic capsule containing estradiol-17 beta (E2) and controls with an empty capsule for 4 weeks. Other rats which received E2 for 4 weeks had the capsule removed and experiments performed 4 weeks later. At the end of 4 weeks of E2 treatment, anterior pituitary (AP) weight was increased sixfold, serum prolactin (PRL) 65-fold, and AP DNA content fivefold over OVX control rats. Four weeks after removal of E2, AP weight, serum PRL, and AP DNA content declined, but remained significantly above OVX control values. At the end of 4 weeks of E2 treatment and after E2 withdrawal, release of [3H]dopamine (DA) from median eminence (ME) tissue superfused in vitro was lower than from ME of OVX control rats although [3H]DA accumulation was not significantly different among the treatment groups. Administration of apomorphine (APO), a dopamine agonist, significantly reduced plasma prolactin levels in OVX control rats, in rats at the end of 4 weeks E2 treatment, and in rats after 4 weeks of E2 withdrawal. Injection of haloperidol (HALO) produced similar increases in plasma PRL/estimated PRL-cell DNA in OVX controls, at the end of E2 treatment or after E2 withdrawal. However, injection of morphine (MOR), a drug which increases the release of PRL by inhibiting hypothalamic dopaminergic activity, resulted in a rise in plasma PRL/estimated PRL-cell DNA in OVX control rats that was significantly greater compared to rats at the end of E2 treatment or after E2 withdrawal. Since rats treated with E2 released less [3H]DA from ME tissue in vitro, and were less responsive to MOR, it can be that animals treated for 4 weeks with E2 show a decreased ability to release DA from TIDA neurons which persists even after termination of E2 treatment. These results suggest that chronic high circulating E2 levels result in a depression of TIDA neuronal activity which is sustained after E2 is removed.
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Pituitary growth hormone and hypothalamic somatostatin in young female rats versus old constant estrous female rats.
Pituitary content and concentration of growth hormone was significantly reduced, and hypothalamic somatostatin content significantly increased, in old constant estrous as compared to young female rats. Increased levels of somatostatin may contribute to the decrease in pituitary growth hormone levels in these animals.
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Growth hormone restores protein synthesis in skeletal muscle of old male rats.
The present study was undertaken to determine if the decline in skeletal muscle protein synthesis with age results from diminished secretion of growth hormone (GH). Young rats (3 to 4 months) were injected with vehicle and old rats (19 to 21 months) with bovine GH (2 mg/kg/day), L-dopa (100 mg/kg/day), or vehicle for 8 days, and the rates of phenylalanine incorporated into total diaphragm muscle protein/ug DNA/unit time were compared. After correction for free phenylalanine specific activity, rates of protein synthesis were determined to be reduced by 26% in old as compared with young rats (p less than .05). Treatment of old rats with bovine GH increased the rate of protein synthesis by 55% when compared with vehicle-treated old rats (p less than .05). L-dopa increased protein synthesis by 22% when compared with vehicle-treated old rats, although this was not statistically different from young or old vehicle-treated rats. These data indicate that (a) there is diminished capacity by skeletal muscle of old rats to synthesize protein; (b) this decrease is related to the reduced GH secretion because protein synthesis can be restored by GH administration; and (c) the dose of L-dopa given, although it increased the levels of circulating GH, did not completely restore protein synthetic capacity.
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Relation of gonadal hormones to differential LH response to naloxone in prepubertal male and female rats.
Naloxone (NAL) has been shown to induce LH release in female but not in male rats 10-25 days of age. The purpose of this study was to examine the role of neonatal gonadal hormones on NAL-induced LH release in male and female rats 15, 25, and 35 days of age. On each of these days rats received a s.c. injection of either NAL (5 mg/kg) or physiological saline, and blood was collected 30 min later by decapitation. At 15 days of age, NAL induced LH release in intact and ovariectomized (OVX) female rats, and in male rats castrated (CAST) on the 1st day of life (neonate CAST males). Injection of 10 micrograms estradiol benzoate (EB) 24 h prior to NAL administration blocked NAL-induced LH release in these rats. NAL had no effect on LH release in 15- or 25-day-old intact and CAST male rats or in female rats given 2 mg testosterone propionate at 3 days of age (androgenized female rats). At 35 days of age, NAL induced LH release in intact, OVX, and OVX-EB treated female rats, and in neonate CAST and neonate CAST-EB treated male rats. NAL had no effect on serum LH levels in androgenized female rats. NAL induced LH release in intact and CAST 35-day-old male rats, but pretreatment with estrogen prevented NAL from eliciting LH release. These results indicate that neonatal exposure to androgen is responsible for the sex difference in the LH response to NAL observed in prepubertal male and female rats before 30 days of age.(ABSTRACT TRUNCATED AT 250 WORDS)
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