Biomarkers of aging and survival kinetics.
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Aging↗
Biomedical subjects
L Piantanelli
Publications and source records attributed to L Piantanelli.
Differential regulation of brain beta-adrenoceptor subpopulations in aging rodents.
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Aging↗
Age-related alterations of isoproterenol-stimulated adenylyl-cyclase activity are partially corrected by thymic graft.
Previous experimental results have demonstrated progressive impairments in beta-adrenergic responsiveness with advancing age. Beta-adrenoceptors are involved in the alterations as their density progressively decreases during aging. Alterations in both in vivo responsiveness and receptor density are corrected by neonatal thymic grafts. In the present paper adenylyl-cyclase (AC) activity has been studied in the same animal models used before. Results show that no statistically significant changes can be observed when AC is assayed in absence of beta-adrenergic stimulation. On the contrary, when assayed after Isoproterenol stimulation, AC activity shows a shift of the peak and a decrease of its height in aged animals. A neonatal thymus grafted into old recipients one month before the experiment was performed, is capable of correcting the altered height of the peak but not the peak concentration.
Adenylyl Cyclases↗
Modelling survivorship kinetics: a two-parameter model.
A mathematical model of survivorship kinetics is presented. It takes into account both deterministic and stochastic aspects of survival curves. Earlier reports [Piantanelli: Arch Gerontol Geriatr 1986;5:107-118; Piantanelli: Ann NY Acad Sci 1988; 521:99-109] described a model capable of making distinct predictions on the mean and standard deviation of an index of physiological function, fitting data even in the tail of survivorship curves, and accounting for the selection of the cohort at advanced ages. However, it contains four parameters whose biological interpretation is unclear. In the present paper we propose a modification of the model which maintains the main characteristics of the previous one and, in addition, results in two significant improvements. First, the number of free parameters is reduced to only two, making much easier both their estimation and interpretation, particularly when the model is applied to data from various animal groups manipulated in different ways. Second, it is possible to relate the parameters to well-defined deterministic and stochastic factors: specifically, a deterministic component describing the environmental and genetic influence on physiological functions, and a stochastic component representing the fluctuating interactions of the living organism and its environment.
Aging↗
Role of triiodothyronine in down-regulation and recovery of lymphocyte beta-adrenoceptors in thyroidectomized patients.
Thyroid function modulates beta-adrenergic sensitivity through the regulation of beta-adrenoceptor density. In particular, thyroidectomy decreases and thyroid hormone injections increase beta-adrenoceptor density on human lymphocytes. In the present paper the relationship between receptor modifications and thyroid hormone levels has been studied in human lymphocytes from patients after thyroidectomy. The patterns of early changes as well as recovery trends have been investigated. Results show a statistically significant fall in receptor density, parallelled by a decrease in T3 levels, 1-3 days after thyroidectomy. Recovery of receptor density is observed 5-8 days after surgical intervention and is accompanied by increased T3 levels. There is a positive correlation between receptor density and T3 levels. On the contrary, no statistically significant correlation was observed for receptor density and T4 levels. The time course of disappearance and recovery of receptor density and that of T3 levels have also been analyzed with the aid of a mathematical model fitting experimental data. On this basis, the hypothesis that both down-regulation and subsequent recovery of beta-adrenoceptor density are driven by the fall and rise of T3 is suggested. Data are also discussed in relation to experimental results we have obtained in animal studies.
Adult↗
Thymus-induced recovery of age-related decrease of brain cortex alpha- and beta-adrenoceptors.
It has previously been demonstrated that thymus exerts a regulatory influence on beta-adrenergic system during aging. In particular, it has been shown that thymus can correct the beta-adrenoceptor density decrease in old mice. In the present paper results of experiments are reported dealing with the influence of the thymus on alpha-adrenoceptors of mouse brain cortex. Both subtypes of alpha-adrenoceptors are studied separately, using different labelled ligands. Results show that alpha 1-adrenoceptor density decreases in old animals, while alpha 2-adrenoceptor density does not change significantly. A neonatal thymus grafted into old recipients is capable of correcting the alteration observed in old mice. The differential impairment of alpha-adrenoceptors resembles that one previously observed on beta-adrenoceptors, where beta 1-type decreases in number during aging with a parallel decrease of adenylyl-cyclase activity, while beta 2-type remains unchanged.
Adenylyl Cyclases↗
Influence of age on the thyroid hormone-induced up-regulation of beta-adrenoceptors in mouse brain cortex.
The influence of ageing on the ability of the brain cortex beta-adrenoceptors to be regulated by very short stimulation with thyroid hormones has been investigated. Experiments were performed in 3-, 10-, 17- and 22-month-old mice using both thyroxine (T4) and triiodothyronine (T3) as stimulators and analyzing beta-adrenergic receptor characteristics 15 and 60 min after hormone injection. Results showed that a statistically significant up-regulation is present in both young and old mice when treated with T3. On the contrary, after T4 injection only 3-month-old animals respond to such a short-term treatment, whereas older adult and old animals showed not statistically significant changes. Thus, the impairment in the T4-induced up-regulation starts already in adult mice and does not seem to further increase progressively with advancing age. From these findings it is suggested that the lack of responsiveness of beta-adrenoceptors to T4 but not to T3 stimulation in adult and old mice may be due to relatively early impairment in the transformation of T4 into T3.
Age Factors↗
Thymic involution and aging processes.
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Aging↗
Ageing and thymus-induced differential regulation of beta 1 and beta 2 adrenoceptors of mouse brain cortex.
Two questions have been addressed by the present paper, that is, the differential influence of age on beta 1 and beta 2 receptors and the thymus-induced recovery of such changes in receptor density and affinity have been assayed in brain cortex of Balb/c-nu mice of different ages. Results have shown a progressive decrease of beta 1 receptor density with advancing age, while no statistically significant changes were observed in beta 2 receptor density. Receptor affinity did not show any changes among the various groups examined. The influence of the thymus on receptor characteristics has been studied comparing young, old and thymus-grafted old mice. Total receptor density, which is decreased in old animals, can be up-regulated by thymus graft in old recipients. Interestingly, such a corrective effect is exerted only on the beta 1 population, the beta 2 receptor not being significantly affected. Thymic graft, therefore, acts just on the population which is found altered during ageing.
Aging↗
Cancer and aging: from the kinetics of biological parameters to the kinetics of cancer incidence and mortality.
Epidemiologic and biological data strongly support the existence of a strict link between cancer and aging. In spite of the relevance of the problem, there were numerous pitfalls in epidemiologic investigation until a few years ago. An apparent decrease of cancer incidence in old age was revealed to be a misconception based on lack of sufficient appreciation for changing population size. But not all problems are solved by using age-specific cancer incidence, as recently stressed by some authors. At very advanced ages a slowing of the rate of increase of age-specific cancer incidence is clearly demonstrated. These findings apparently clash with the majority of biological data and suggest that some mechanism may develop at advanced ages capable of decreasing cancer susceptibility. In this paper, it will be shown that just a slowing-down kinetics is predicted for cancer incidence by using a mathematical model of mortality kinetics recently proposed in the gerontologic field. The slowing of the increasing rate or even a decreasing trend of cancer incidence of an aging population is compatible with a continuously accelerating pace of loss of physiological capacity of the single subjects, as with advancing age there is a selection of individuals with better physiological functions.
Adult↗
A mathematical model of survival kinetics. I. Theoretical basis.
A mathematical model of mortality and survival kinetics is proposed based upon the two main aspects of survival data, namely, the rate of vitality reduction with age and its statistical distribution. Certain mathematical assumptions are made on the time-course of both vitality and its distribution. Then, these two aspects are integrated in a single model which can be used to describe survivorship, cumulative mortality or dying. The model is capable of fitting empirical curves even at very advanced ages, where the widely used Gompertz law fails. Examples are provided, derived from populations having rather different lifespans such as rotifers, flies, rats and horses. The model maintains one of the most interesting characteristics of Gompertz law, namely, the possibility to estimate the 'design constant for longevity' relating maximum lifespan to one of the parameters of the model. It also has the potential characteristics enabling it to be used to judge the statistical significance of the difference between two empirical survival curves.
Aging↗
A mathematical model of survival kinetics. II. Parameter estimation.
Procedures for the estimation of the four parameters of a new mathematical model of survival and mortality kinetics are given. A formulation of the model has been found which had the advantage of maintaining three of four parameters independent of the unit chosen for the age; in addition, two of these parameters have values falling in a narrow range, even when the model is applied to rather different curves. Since, in any problem of this type, the initial estimate of the parameters plays a major role in the achievement of good final estimates, some simple methods of estimation are indicated based upon the characteristics of the function. The initial estimates may enter three different types of procedures; the best one can be chosen according to the precision of the initial estimates. The method is capable of fitting both survivorship and dying functions directly to the empirical data. An interactive approach to the computer facilities has been used as at each step the operator has to decide whether or not to apply a corrective factor. Goodness of fit, usually high, is estimated by chi 2 test.
Aging↗
Impaired adaptive receptor regulation: an index of aging?
Many neuroendocrine functions are altered in old animals and their study may represent important steps in the understanding of the mechanisms of aging. A deeper insight, however, can be achieved by investigating the responsiveness to stimuli, which may reveal alterations not evident in the unstimulated conditions. At this level of study, many of such impairments have been found to be caused by receptor changes. In the present paper a third level of study is suggested in order to gain evidence of some remote failure of adaptive processes strictly linked to intimate mechanisms of aging. As at the second level of study different receptor characteristics can frequently be found at the basis of age-related alterations of biological responsiveness, at the proposed third level altered capacity of receptor regulation may be hypothesized as responsible for altered cell adaptation following hormone and drug stimuli. Experimental data are given which support this view. The possibility that receptor regulation may be used as an index of aging is suggested. This hypothesis leads to the problem of judging the validity of biological parameters deputed to represent good indices of aging. In order to solve this problem, the potential use of a mathematical model of mortality kinetics is discussed.
Adaptation, Physiological↗
Thymic regulation of brain cortex beta-adrenoceptors during development and aging.
The influence of the thymus on beta-adrenoceptors has been studied in the brain cortex of mice during developing and aging. Affinity of beta-adrenoceptors shows no statistically significant changes in the various animal models investigated. Receptor density shows a fall in both athymic nude mice and in old normal mice. Receptor density, in particular, decreases progressively with advancing age. It has been demonstrated that thymus exerts a regulatory role in both development and aging, as a neonatal thymic graft is capable of reversing the receptor impairments found in young athymic nude mice and in old normal mice.
Aging↗
Acebutolol-induced decrease of mononuclear leukocyte beta-adrenoceptors in hypertension.
The regulatory action exerted on receptors by acebutolol, a cardioselective beta-blocker containing intrinsic sympathomimetic activity, has been investigated. beta-Adrenoceptor affinity and density of human mononuclear leukocytes were assayed in hypertensive patients before and after treatment with 400 mg/day acebutolol. While receptor affinity showed no changes between pre- and post-treatment values, a statistically significant decrease has been demonstrated in receptor density following treatment. Blood pressure and heart rate were also measured in order to test the efficacy of the administered drug. All these parameters showed a fall in the post-treatment values. It is concluded that the partial agonist acebutolol, in spite of the fact that it acts clinically as a beta-blocker, has the regulatory mechanism characteristic of agonists.
Acebutolol↗
[The role of neuroendocrine-immunological interrelations in the development of tumors].
There is at present an experimental evidence of neuroendocrine-immunological interactions in tumor development both in experimental models and man. In fact, different hormone receptors have been found in both experimental and spontaneous tumors in animals and man. Such tumors are therefore under the influence of the neuroendocrine system. In addition, some hormone-metabolic alterations such as those observed in advancing age are often associated with a high incidence of the neoplastic growth. Interestingly, tumor incidence increases with advancing age in both man and animals and experimental tumors are more easily transplanted in old mice than in young adult mice. On the ground of these observations it can be suggested that tumor growth results from the interactive action of both the immunological and neuroendocrine systems.
Adrenal Glands↗
[The endocrine thymus. Changes in its efficiency as a function of age].
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Age Factors↗
Age-dependence of isoproterenol-induced DNA synthesis in submandibular glands of BALB/c mice.
The age-dependency of isoproterenol (IPR) induced DNA synthesis was investigated in different organs of Balb/c mice. Although modifications of the physiological rate of DNA synthesis after IPR injection occurred also in liver and spleen, a quasi-linear decrease of the peak of IPR response with advancing age was observed only in submandibular glands. Such a decrease was observed when animals were injected with 10(-4) g IPR per g body weight, lower doses being unable to discriminate between young and old mice. In spite of some differences between mice and rats, the early appearance and linearity of the age-dependency remain common features of IPR response.
Age Factors↗