An article by Dr. Walter Pierpaoli
The pineal gland and "neuro-immunomodulation of aging": an inborn program
The three models developed in order to evaluate whether or not the progressive alteration of pineal function in the course of aging is in fact a possible cause of aging, were based on the consideration that if the pineal gland, thanks to its known bidirectional linkage with the entire neuroendocrine system, is the "master gland" of the body, its own progressive "aging" in the course of life may result in the de-synchronization of all functions and in particular of those metabolic pathways which maintain the integrity of the neuro-hormonal (endocrine) and of the immune systems. Although we still do not know why the pineal gland itself ages, we have demonstrated that the pineal gland and at least one of its products, namely melatonin, are key elements to start understanding why we age. It is in fact beyond any doubt that a very significant aging postponing effect is achieved in aging mice (and rats) with nocturnal administration of melatonin or young-to-old pineal grafting (11,12,16-19,23-25). However, an even more remarkable observation derived from the young-to-old and old-to-young, pineal cross-transplantation model, which revealed that an acceleration of aging is achieved when a younger animal is grafted with an older pineal gland after removal of its own pineal (6). This striking finding opened to us an unexpected field of investigation. It seems in fact that, after a certain age, the pineal gland actively promotes aging, as if the inborn program for pubertal maturation and reproductive function would inevitably lead to another step of the maturational events, namely aging.
This is even more evident if we consider that the implantation of a young pineal gland into the thymus of older mice does not result into any life prolongation if the recipient is too old (unpublished). It means that once the endogenous pineal has aged, no intervention can prolong life. There exists a critical age in pre-senescent or definitely senescent mice when both pineal grafting or melatonin administration affect positively the life span. But beyond a certain age, apparently the old mouse owns pineal determines itself the termination of life. This is clearly shown by the acceleration of aging in pinealectomized young mice implanted with an old pineal gland (6) but even if a normal; non-pinealectomized young mouse is implanted with the pineal gland from a very old donor mouse. This extraordinary observation forced us to recognize that there might exist a "death clock" in the pineal gland whose "program" cannot be modified unless the aging pineal is removed in due time and replaced with a younger pineal. We are thus in front of a completely new element for the evaluation of the causes of aging and of the significance of biological death. We can infer that the pineal gland, at least in our experimental models with rodents, is at the same time an "aging clock", a "life clock" and a "death clock", depending on its chronological stage from birth to death. If this is the case, a large number of experiments are needed to assess these crucial temporary steps in mammals, man included. This is even more relevant than the further work aimed at the investigation of the mechanisms, or they should proceed in parallel with those studies. We are generally prone to study the details before understanding how the pineal gland itself, thanks to its links to the entire neuroendocrine network, programs aging. In the next section I will suggest some of the investigations which, in my view, must be carried out in order to decipher some basic aspects of pineal aging on the basis of our earlier and current findings.
The rotation theory of aging: what needs to be done now? Here are a few examples.
A) Pinealectomy at different ages. If the pineal gland is a chronological scanner of growth, puberty, fertility and finally aging, we must perform extensive experiments of pinealectomy in rodents, in order to evaluate whether the consequences of pinealectomy will differ depending on the age when removal of the gland is performed. It is in fact obvious that the consequences of pinealectomy may be profoundly different or even negligible depending on the age and sex of the animals. We have observed that the thermocoagulation (cauterization) procedure is not adequate to remove the pineal gland. Surgical removal of the entire pineal gland with its stalk is mandatory and its complete absence must be confirmed at autopsy and by histological analysis. Other methods have given us contradictory and unclear results. Some preliminary results indicate that removal of the pineal gland in senescent animals may be beneficial. If this is true, it would confirm our concept that the pineal actively promotes aging when the "clock" of life has expired its genetically programmed cycle. A very extensive number of measurements must be carried out in order to evaluate the cause and the sequence of the derangements affecting immunological and neuroendocrine functions. It may be possible that pinealectomy at a young age does not affect the life span simply because compensatory mechanisms, (e.g. other sources of melatonin) adjust the body to the removal of the pineal. This could be completely different later in life or at the time of aging. The blunting or decrease of the night peak of melatonin in the course of aging could be only a signal of pineal aging and the initiation of active death signals.
B) Pineal grafting in normal or pinealectomized, young, adult or older recipients. Experiments should be carried out in large groups of male or female mice and rats of different age, in order to evaluate if pineal grafting from a young or from an older donor into their thymus or under their kidney capsule would affect their aging. This approach would help understanding to what extent chronological aging of both the implanted pineal gland and of the grafted normal or pinealectomized young or old recipients, would delay aging and/or prolong their life span.
C) Multiple and repeated pineal grafting into aging, intact or pinealectomized animals. Pinealectomized and normal, intact aging mice and rats should be implanted into the thymus with a pineal gland from young donors and transplantation of the young pineal from the young syngeneic donor should be repeated and a new gland grafted again into the thymus or under the kidney capsule of the same recipients about four-five months later. Grafting should be repeated again in case an aging-postponing effect is visible and measurable. This intervention could indicate if the limited duration of the aging-delaying effects of young-to-old pineal grafting depends on a progressive expiration, deterioration or aging of the intrinsic activity of the young, grafted pineal, which must be replaced with a new young pineal in order that the aging-delaying activity can be further prolonged.
D) Seasonal variability of melatonin administration. It is of paramount relevance to evaluate the aging-postponing effects of nocturnal administration of melatonin to old mice and rats in relation to the season. This is particularly easy in rodents, whose life span is about two-three years and whose physiology (immunity, hormonal and reproductive functions) is profoundly influenced by the season, in spite of their maintenance under constantly artificial conditions of light and temperature. Experiments should be devised where the animals are maintained from birth under natural seasonal variations of light and temperature, in special and protected (low-stress) cages where natural cyclicity of environmental factors is much closer to the conditions of wild animals. We have observed a striking, aging-delaying effect of melatonin when given during four winter months (from November until February) to aging mice (unpublished). Although these effects may not be so relevant in man, their interpretation would be very useful for improving the beneficial activity of nocturnal melatonin administration in man.
We just skimmed over the many, almost unlimited work which must be done before we can start to examine closely the mechanism of action of melatonin. It is in my view illusory the pretence to elaborate a "mechanism" until we have done the basic "dull" work which could clarify to us whether or not there is a centralized "aging and/or life clock" in the mammalian pineal gland which is amenable to a pharmacological or physiological modulation.
