in producing disease cannot be doubted, and Sir Arbuthnot Lane[126]
has brought this prominently to our notice; while clothing in modern
language the old ideas of the _primae viae_ he recalls to our memory
Abernethy’s[127] panacea for many ills of the flesh, namely a blue pill
at night followed by a mixture of gentian and senna in the morning.
Among his collaborators Mr. Ernest Clarke[128] has insisted on the
premature ageing of persons with intestinal stasis. From the analogy
of syphilis, alcoholism, and other intoxications, which may produce
degenerative changes simulating those found in old age, the hypothesis
of intestinal toxaemia gains a certain amount of support, and it may
not be so easy to exclude the agency of intestinal toxaemia as in the
case of syphilis and some intoxications. But intestinal toxaemia may,
as far as can be judged, be absent in healthy old age, and conversely
be present in early life without causing the phenomena of old age.
Further objections have been raised:--why should intestinal toxins be
harmless for 40 or 50 years and then exert such a serious influence?
why should women who are more subject than men to constipation be
more long-lived; and that in constipated persons the faeces, as shown
by Schmidt and Strasburger, contain fewer living bacteria than in
health.[129]
As applied to normal old age and death this hypothesis is pathological
and therefore has rather failed to interest those who are working at
the biological aspect. Perhaps the most that can be safely concluded
in balancing the pathological and biological arguments is that while
Metchnikoff’s view may be partially true it does not account for
all senile changes, and that normal old age or senescence cannot be
regarded as the result of toxins absorbed from the alimentary canal.
OLD AGE OF CELLS AND CARCINOMA
The relation between ageing of the cells on the one hand and the
development of carcinoma on the other hand is a subject of great
interest. According to Karl Pearson’s[130] statistical enquiry the
incidence of carcinoma reaches its maximum at the age of 46 years in
women and 56 years in men; Lazarus-Barlow[131] concluded that the
range of years over which cancer is likely to occur is practically the
same in the two sexes, namely 46 to 64, and that among 4659 cases of
malignant disease there were only 35, or 0·7 per cent, over 80 years
of age.[132] The cancer age, therefore, coincides with the waning of
maturity and the onset of old age; that carcinoma is rare in very
old persons is also shown by the occurrence of one case only among 71
centenarians collected by Sir George Humphry. Laurent[133] considered
that whereas longevity depends on a condition of vital equilibrium,
the development of cancer is due to a want of this equilibrium, to a
state of anarchy, and that the factors disposing to orderly vitality
are conducive to longevity and antagonistic to the development of new
growth. The reason why malignant growths are prone to appear with
the onset of old age has naturally been the subject of much debate.
According to Thiersch degeneration lessens the controlling influence
normally exerted by connective tissue on epithelium, the inherent
proliferative capacity of which then runs riot. Ribbert believed
that from loss of resistance or diminution of surface tension in the
connective tissues post-natal “rests” of epithelium were produced
as the result of irritation and that these displaced cells then
grew because there was no controlling opposition. Adami suggested a
reversion of the highly specialized epithelial cells to a simpler form
with powers of proliferation, the cumulative habit of growth taking
the place of the habit of work, and practically anticipated the more
modern view. According to Hastings Gilford[134] malignant disease is
a premature cell senility and the result of the partial reversion of
immature or adult cells to an embryonic or quasi-embryonic state.
From a study of senescence in dogs Goodpasture[135] concludes that
degenerative changes in the cells lead not only to death of some
cells but to dedifferentiation of others, which, becoming simpler in
structure and function, recover their juvenile power of growth in
varying degrees, and that hence metaplasia and tumour growths occur as
accidents of commencing old age. A little later Oertel[136] insisted
on his view that cancer is not an embryonic reversion or a specific
change in the cell but a phenomenon of senescence--a degenerative
proliferation depending upon disturbances in the nucleus plasma
relations, specifically upon the loss of nuclear chromosomes; from age
or degeneration the tumour cell loses the higher functional chromosomes
and retains the genetically older and more resistant ones controlling
reproduction and vegetative activities; thus there arises a race of
cells without the differentiation of undegenerated cells.
These various expressions of opinion would justify the conclusion that
with the onset of old age the degenerative processes in the cells lead
to the production of less specialized cells which have the compensating
property of more vigorous growth, and that in certain circumstances,
one of which is very probably a diminished power of resistance on the
part of the surrounding tissues and another, and very important one,
irritation in some form or another, riotous proliferation of the cells
invades the adjacent parts. That the conditions necessary are usually
local is strongly suggested by the appearance of the new growth at one
spot only and by the frequent absence of recurrence after free removal.
There may be a premature local senescence of the tissues, just as there
is premature old age of the body generally, and this would explain
the exceptional occurrence of malignant disease in early life or long
before the usual time.
VI
NORMAL STRUCTURAL CHANGES IN OLD AGE
Physiological old age, namely a process of involution and atrophy
uncomplicated by superimposed pathological changes, is extremely
rare; pathological processes may initiate and hurry on a condition
imitating old age, and indeed the morbid changes found after death in
old people commonly show the lesions of past infections in addition
to those of physiological involution, and the longer life lasts the
greater the probability that changes due to disease will accumulate.
It is therefore difficult to determine accurately where physiological
involution ends and pathological lesions begin, and there has been much
confusion between physiological old age and pathological senility.
It must, on the other hand, be admitted that the ideal condition of
physiological involution without some definite evidence of superadded
pathological change hardly ever comes before us. In fact at the best
old age is almost always but relatively physiological, in other words,
as Metchnikoff wrote in 1903, there is at present, from the conditions
of inharmonious environment, no chance of a really physiological old
age and death for mankind. But the view that old age is invariably the
accumulated product of multiple injuries due to infection and poisons,
or that it is due to arteriosclerosis (Boerhaave, Haller, Demange) is
an entirely different proposition and does not fit in with biological
knowledge. While fully recognizing the difficulties an attempt may be
made to tabulate the natural changes accompanying and responsible for
old age, and to contrast them with the pathological changes commonly
complicating the normal structural involution of the human body.
The general atrophy of old age, as grossly shown by loss of weight,
does not proceed equally in all parts of the body. The supporting
fibrous tissues of the body and organs certainly atrophy less than
the nobler, because actively functional, cells of the organs; it is
difficult to estimate the atrophy of the fibrous tissues, for from
shrinkage of the parenchyma of organs and of muscles the fibrous
framework stands out in greater prominence. Some proliferation or
replacement fibrosis follows atrophy of the nobler tissues, and
pathologically infection may cause fibrosis. But that the fibrous
tissue does to some extent share in the general atrophy is rendered
probable on the analogy of the change in the allied tissue of bone
which undergoes rarefaction and thinning. The subcutaneous and
perivisceral stores of fat diminish out of proportion to the fibrous
supporting tissues around them. The place of the fat in the fat cells
may be taken by fluid--serous atrophy--or the cells may simply revert
to the condition of connective tissue cells. In passing it may be
pointed out that it is curious that with the diminished metabolism of
old age the stores of fat are not increased as they are in similar
circumstances in adult life; Is it due to a widespread atrophy of the
connective tissue cells that store fat? If so, an accumulation of fat
in the liver might be expected, but this is not so. Possibly it is the
result of deficient assimilation. The heart, as Councilman[137] has
shown, is on the whole better preserved than the other organs; but it
might well be argued that the existence of such a cardiac condition is
a determining factor in the attainment of advanced age.
_The skin_ is dry, thin, smooth, glossy from atrophy, inelastic like
parchment, and is wrinkled from degeneration and disappearance of the
elastic tissue, subcutaneous fat and muscular fibre. These changes
are most advanced on the face, especially the forehead, and backs
of the hands from exposure. The degeneration of the elastic fibres,
recently studied by Kissmeyer and With,[138] gives a characteristic
mesh-like appearance, depending on the rigid wrinkles, to the skin,
which takes a yellow tint. The ivory pallor and coldness are due to the
diminution in the capillaries; the skin may show areas of pigmentation
and leucodermia--changes described by Sir Lenthal Cheatle as due to
the wear and tear of life (biotripsy); in a woman aged 93 Salimbeni
and Gery described almost complete disappearance of the papillae
and of the collagen fibres. The pigmentation has been regarded as a
means of protection, for there is a relation between it and malignant
disease, the latter being prone to occur when pigmentation fails
(Pringle[139]). These atrophic changes are far commoner on the backs
than on the palms of the hands, and it is noteworthy that among
Cheatle’s[140] 200 collected cases of malignant disease of the hand
there was one only on the palm. The subcutaneous fat is diminished in
amount, which is regarded by Sir Arbuthnot Lane, though not with any
special reference to old age, as one of the many results of colonic
toxaemia. The yellow fat contains excess of cholesterol. There is
diminished secretion by the sweat and sebaceous glands, and from this
cause and the diminished vascularity there is less loss of heat to
correspond with the slower metabolism.
_Hair._--Greying or whitening of the hair occurs commonly in old age,
but not universally for some centenarians have retained the natural
colour of the hair; coarse jet-black hair is specially prone to whiten
early. The change in colour has been ascribed by Metchnikoff to the
action of phagocytes (chromophages) which invade the roots of the hairs
and carry off the pigment granules. Like the arcus senilis it may occur
quite early in life and without any other indication of age, and is
often hereditary; as the sage of Norwich wrote, “Hairs make fallible
Predictions, and many Temples early Gray have outlived the Psalmist’s
Period.”[141] Lord Bacon[142] indeed said, “Hasty gray hairs, without
baldness, is a token of long time; contrarily, if they be accompanied
by baldness.” But baldness is often due to seborrhoea and so only
secondarily connected with advanced age. In some rare instances the
hair already grey or white has been known to regain its normal colour;
the late Sir Charles Cameron[143] recorded this event in his own life
after an accident confining him to bed for some months in his eightieth
year, and refers to the hair of a man aged 90 years returning to
its original brown colour; cases were also reported by Graves.[144]
Velasquez de Tarente[145] recorded an abbess who after an illness which
promised to be fatal in her hundredth year had a crop of brown hair,
and, like Sir Charles Cameron, put on weight. Four other cases are
given by Sir John Sinclair[146] in persons aged 80, 104, 105, and 114
years. Baldness may be definitely due to thyroid insufficiency and not
to atrophy of the hair follicles and sebaceous glands.
A pensioner aged 75, whom I saw with Major R. J. C. Thompson,
in the Royal Hospital, Chelsea, with baldness and a grey
beard, was given thyroid extract, as he was thought to
have hypothyroidism; his general condition then improved
wonderfully, and his scalp became covered with dark brown hair
which had to be cut at intervals. Parkinsonian tremor was
rather more obvious during the first six months that he was on
thyroid treatment.
The hair of the body may become scanty and lose its tendency to curl.
Excessive growth of hair (hypertrichosis) in women after the menopause
is an indication of disordered endocrine balance (loss of ovarian
internal secretion?) and is only so far an accompaniment of age; it may
be seen in comparatively young women from various causes.
_The nails_ are often longitudinally ridged, brittle, hard, and
thickened; but onychogryphosis is rather the result of neglect or of
disease than solely of old age.
_The brain_ as a natural result of atrophy becomes lighter; Boyd’s[147]
tables show that the male brain is 3 oz., and the female brain 4
oz., lighter in persons over 80 years of age than in the decade 20 to
30. The convolutions, therefore, become separated and the amount of
cerebrospinal fluid greater. The atrophy is not uniform, being less
in the posterior third than in the anterior two-thirds. The nerve
cells become smaller, pigmented, and degenerate. The brain is said
by Cerlette to be affected by a process special to old age--miliary
necroses scattered over the cortex and associated with changes in the
small arteries which show remarkable knots; a condition which suggests
a pathological softening secondary to arteriosclerosis, especially
as the change does not come on constantly at a definite age period.
Cavities with thickened walls, possibly due to miliary haemorrhages,
or to softening around the vessels are also described. Metchnikoff’s
description of phagocytic destruction of the nerve cells by macrophages
has been seriously questioned and thought to be based on erroneous
observation, the glia cells being regarded as macrophages (Marinesco).
The spinal cord shows an increased number of amyloid bodies, some
diffuse sclerosis, often obliteration, by epithelial proliferation, of
the central canal, and atrophy with pigmentation of the nerve cells,
especially in the anterior cornua. The membranes may contain small
calcareous plaques.
_The arcus senilis_, due to infiltration with fats, especially
cholesterol and lipochrome, and to degeneration of elastic tissue at
the periphery of the cornea, is often associated with arteriosclerosis
(Monauni[148]). It is not a necessary accompaniment of age; among 321
persons over 80 years of age, it was absent in 114, or 35·5 per cent
(Humphry); and it is well known that like grey hair, it may occur
in those young in years. Nascher,[149] the author of _Geriatrics_,
had an arcus senilis as a schoolboy. Rigidity and flattening of the
crystalline lens lead to presbyopia, which may be premature and due to
toxaemia, among the causes of which Ernest Clarke[150] gives intestinal
toxaemia a high place. The power of accommodation is also impaired by
weakness of the ciliary muscle brought about in the same way.
_Skeleton._--The atrophy characteristic of senescence is well shown
in the fixed tissues of the bony skeleton. Though the bones do not
as a rule alter materially in size or shape, they do so markedly in
substance from rarefaction and absorption, the latter taking place
mainly from the inside of the bones and especially the cancellous
tissue, the medullary cavity and the Haversian canals becoming larger
(senile osteoporosis). Hence fractures near the joints, particularly
intracapsular fracture of the neck of the femur, are favoured. The
absorption of the alveolar border of the jaw is intimately connected
with the loss of the teeth, and brings the mental foramen to the top
of the edentulous mandible. The angle of the jaw at the junction of
the body and the ramus now opens out and comes to resemble that of an
infant. It is often stated that the angle of junction of the neck and
shaft of the femur becomes less, more of a right angle, but Humphry
regarded this as exceptional.
From muscular weakness the back becomes bent and as a result the
vertebrae become altered in shape. Ossification of the anterior common
spinous ligament--a change analogous to rheumatoid osteophytes around
the more movable joints--is an added and not uncommon change but, like
calcification of the costal and laryngeal cartilages, it is a morbid
process, and when advanced constitutes spondylitis deformans. The
intervertebral discs undergo some loss of elasticity and atrophy,
thus contributing to the loss of height. The cranial bones are usually
thinned, and the parietal bones may show symmetrical or nearly
symmetrical oval areas of excessive absorption of the outer and even of
the inner table, so that the epicranium and the dura mater may be in
contact. These areas which are close to the longitudinal fissure must
not in the case of ancient skulls be mistaken for examples of early
trephining. The bony sutures tend to become obliterated. Instead of
thinning and loss of weight the skull, especially the vault, may show
thickening and be heavier than normal--a change involving chiefly the
inner surface and ascribed by Sir George Humphry to shrinkage of the
brain.
Calcification of the costal and laryngeal cartilages, which have
a yellow tint from fatty change, is, like a similar change in the
arteries, pathological and not part of the process of senescence. Thus
among 10 recorded necropsies on centenarians the costal cartilages were
calcified in 2 only. Calcification of the costal cartilages interferes
with the respiratory movements and was regarded by Sir George Humphry,
who tested for it by estimating the elasticity perceived when gentle
pressure is exerted on the lower part of the sternum, as a bad omen
for the future.
_The teeth_ are usually, but not invariably, few in the aged, for care
or lack of it, the accumulated effect of long-continued mechanical
injuries, altered calcium metabolism, and diminished resistance to
infection will necessarily influence the amount of decay. Statistics,
especially Humphry’s, show that in extreme old age very few teeth are
present, and it is tempting to correlate the diminished provision for
mastication with the lessened need for food. Sir Isaac Newton, however,
at the age of 85 was said to have lost one tooth only. The numerous
reputed instances of a third dentition can be explained only by the
appearance of a previously buried tooth through the atrophying gums,
for a genuine third dentition would necessitate the presence of dental
germs which do not exist.
_The gastro-intestinal tract_ shows atrophy of the muscular coat and
its secreting glands, so that dilatation of the thin-walled, pale
stomach and colon occur on less provocation than in adult life and
digestion is impaired; from lack of mucous secretion combined with
loss of motor vigour constipation is common. It may be added that
hypertrophy of the prostate by interfering with peristalsis of the
colon has been thought to cause gerontal constipation (Hollis[151]).
The pancreas shows fibrotic atrophy and becomes smaller and harder.
From the loss of fat and muscular atrophy visceroptosis is not uncommon.
_The liver_ diminishes in size and weight by about one half; atrophy
of considerable areas may expose the vessels and ducts on the surface
of the organ. Boyd’s tables show a difference of 18 oz. between
the weights in persons in the decade 20–30 and in those over 80.
Microscopically atrophy of the lobules and of the cells in the
centres of the lobules have been described (Luciani[152]), but the
latter change is not constant, for in a woman of 93 Salimbeni and
Gery[153] definitely noted that the cells were not atrophied. That
such atrophy of the liver cells is pathological is perhaps supported
by D. Symmers’s[154] observation that in the pancreas of such cases
the islands of Langerhans may show moderate enlargement, as if to
compensate for failure of the glycogenic function of the liver.
Pigmentation of the cells by a lipochrome is excessive, and the name
brown atrophy has been applied to the condition which is seen in the
other viscera of the old.
_The lungs_ become smaller, lighter, and the elastic tissue
degenerates; this is atrophous emphysema, and the chest capacity
diminishes. Roussy and Leroux[155] found that these lungs commonly
show endarteritis obliterans and fibrosis, conditions which favour
infarction, infection, and the terminal bronchopneumonia to which the
aged are so prone.
_The voluntary muscles_, according to Durante,[156] contain many fibres
with large globules of fat; but Jewesbury and Topley,[157] who describe
coarse fat globules mingled with brown pigment in the immediate
neighbourhood of the muscle nuclei in 50 per cent of cases of various
kinds, and almost constantly in old subjects, regard this condition as
independent of true fatty degeneration, and are doubtful if it has any
pathological significance. Excessive fatty and fibrotic change is found
in cases of senile paraplegia without any lesion in the spinal cord or
brain.
_Heart._--Some difference of opinion exists as to the condition of
the heart; Parkes Weber[158] says that the only true senile change
is diminution in size and weight; this as it is worded is no doubt
correct; but pure atrophy is less rare in the heart than in most parts
of the senile body. Charcot[159] indeed stated that it does not atrophy
in old age, but preserves the dimensions of middle life. The heart may
even hypertrophy in old people; this is pathological; Councilman[160]
found it in 248, or 43 per cent, of 580 persons over 60 years of age,
and could not refer it to aortic or renal arteriosclerosis or to the
diminished capillary area in the skin; but the average blood pressure
158 systolic/88 diastolic of the cases with cardiac hypertrophy was
higher than that 130/78 of the others.
Fatty degeneration of the myocardium is very frequent; Charcot stated
that at the Salpêtrière it was almost constant in old women, but
according to Councilman there is no clear evidence that it produces
permanent injury or functional insufficiency; he noted some fibrosis
in 15 per cent of his cases. Atrophy of the epicardial fat--serous
atrophy--is common, and increase of the so-called lipochrome pigment in
the muscular fibres which become smaller and fewer--brown atrophy--is
frequent as it is in the other organs in old age.
Chronic valvulitis and subendocardial fibrosis are, like
arteriosclerosis, common morbid changes.