In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on (...) this debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

My chief object in these notes is to provide evidence for tracing the ancestry of certain themes, situations, and characters which appear in New Comedy; I hope, however, that they may also be useful for the study of Middle Comedy itself. I am therefore chiefly concerned with the period from 400 b.c. to 320 b.c., when Menander had begun to write; I have, however, given some dates after 320 which were necessary to complete my story, but I have left out (...) many plays by poets of New Comedy which can be dated in the decade 320–310 b.c. I have also omitted the originals of Plautus Amphitruo, Persa, and Menaechmi, although I am convinced that they all belong to Middle Comedy and hope to consider the problem more fully elsewhere; the tactics of the battle in the Amphitruo are possible for Epameinondas and Philip as well as for Alexander, but the clash of two kings seems to limit the reference to Alexander and Dareios as depicted in the famous mosaic, and the limits are 330–320 ; the original of the Persa must have been written before Alexander's conquests and the limits seem to be 345–338; Hueffher's late dating of the original of the Menaechmi has been successfully countered by Fraenkel and the whole feel of the play suggests Middle rather than New Comedy. The following list is arranged in decades, except where it has proved necessary to use a longer period. I have tabulated first the plays or victories dated by inscriptional or other firm evidence; among these I have included the plays dated by Geissler, without comment except where I disagree with him. (shrink)

Professor Beare has attacked the position established by Alfred Körte in 1893 and accepted in large measure by Sir Arthur Pickard-Cambridge in Dithyramb, etc., and Festivals. The following reply is brief because I have dealt with the works of art at some length in Rylands Bulletin, xxxvi , 563 f. and in a forthcoming number of Ephemeris Archaiologike. The statement of Aristotle . I have tried to show that various elements in the ‘phallic performances’ were taken over by comedy and (...) that we have some evidence that the leaders of padded dancers wore the phallos. (shrink)

Greek art and literature follow parallel courses through the long period from Homer to Euripides. Homer and Euripides, Dipylon vases and the latest white lekythoi are as far apart from each other as it is possible for works in the same medium to be. The distance can only be explained by a similar change in the views of artists, writers, and their public.

In The Theatre of Dionysus in Athens Dr. Pickard-Cambridge includes a most useful and convenient collection of south Italian vase-paintings which have been held to throw light on the stage-settings of Greek tragedy. He concludes that they give no evidence for Athens in the fifth century and in particular do not justify the assumption that interior scenes were played in a porch in front of the central door. The second conclusion is true, but some of the vases do show that (...) the central doors could be thrown wide open to display an interior scene. The first conclusion is formally correct, but it should be remembered that the “plays came from Athens, and it is at least possible that the south Italian producers modelled themselves on Athenian producers. In any case these vases are worthy of further consideration. (shrink)

Thomas Bertram Lonsdale Webster. the Persians decided on the best form of government in 520 B.C., but it is far more likely that the discussion reflects political theorising at Athens where he was writing during the contest for power between ...

Greek tragedy is still acted in the original and in translations; it has inspired such modern drama as The Family Reunion and La Machine Infernale; in Norway and France Sophocles’ Antigone helped to give hope to the resistance. Greek tragedy was produced originally at a religious festival by a poet who was poet, musician, producer, and sometimes actor too. The plays were meant to be seen; they had staging and costumes, dancing, and dramatic technique. They were meant to be remembered; (...) they had language, style, and thoughts which the poet desired to communicate at that particular time. The poet himself knew well the leading artists, thinkers, and politicians of the small society in which he lived. Production, metre, technique, style, and thought are the chief elements which the scholar must study if he would make these ancient plays as intelligible as possible to modern readers. (shrink)

A recent report by Tyner et al.1 suggests that p53 is bad for longevity. Heterozygotic mice carrying a p53 mutation that apparently enhances the stability of the wild‐type protein showed shorter lifespans and faster ageing while also developing fewer tumours. This fits with the idea that cellular ageing is the price paid for better protection against unlimited proliferation of cancer cells. But other work shows that there is a strong positive association between DNA repair‐mediated protection against cancer and ageing. So (...) what are we to make of the new data with regard to overall understanding of the mechanisms of ageing? BioEssays 24:577–579, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Human life expectancy has increased dramatically through improvements in public health, housing, nutrition and general living standards. Lifespan is now limited chiefly by intrinsic senescence and its associated frailty and diseases. Understanding the biological basis of the ageing process is a major scientific challenge that will require integration of molecular, cellular, genetic and physiological approaches. This article reviews progress that has been made to date, particularly with regard to the genetic contribution to senescence and longevity, and assesses the scale of (...) the task that remains. (shrink)