A woman feels so nervous as she will turn 55 years old this year.

She realizes that her

aging process is more obvious. She feels not as pretty as before, her skin looks more

'saggy'/slacker, especially around the eyes. She has lost her weight, so that her body shape

seems smaller. She suffers blurred vision, hearing loss, easy to fall, especially from sitting to

standing. She feels so dizzy and imbalance. She also hasn’t got her period since 5 years ago. She

read on the internet, and it is said that the aging process resulted from various factors that

involving many theories. Despite her anxiousness about her condition now, she feels quite

confident that she can undergo this phase by adopting a healthy lifestyle & keeping her social life

good.

1. She realizes that her aging process is more obvious

Proses penuaan biologis ini terjadi secara perlahan-lahan dan dibagi
menjadi beberapa tahapan, antara lain:14
1. Tahap Subklinik (Usia 25 – 35 tahun):
Usia ini dianggap usia muda dan produktif, tetapi secara biologis mulai
terjadi penurunan kadar hormon di dalam tubuh, seperti growth hormone,
testosteron dan estrogen. Namun belum terjadi tanda-tanda penurunan
fungsi-fungsi fisiologis tubuh.
2. Tahap Transisi (Usia 35 – 45 tahun):
Tahap ini mulai terjadi gejala penuaan seperti tampilan fisik yang tidak
muda lagi, seperti penumpukan lemak di daerah sentral, rambut putih
mulai tumbuh, penyembuhan lebih lama, kulit mulai berkeriput, penurunan
kemampuan fisik dan dorongan seksual hingga berkurangnya gairah hidup.
Radikal bebas mulai merusak ekspresi genetik yang dapat bermanisfestasi
pada berbagai penyakit. Terjadi penurunan lebih jauh kadar hormon
hormon tubuh yang mencapai 25% dari kadar optimal.
3. Tahap Klinik (Usia 45 tahun ke atas):
Gejala dan tanda penuaan menjadi lebih nyata yang meliputi
penurunan semua fungsi sistem tubuh, antara lain sistem imun,
metabolisme, endokrin, seksual dan reproduksi, kardiovaskuler,
gastrointestinal, otot dan saraf. Penyakit degeneratif mulai terdiagnosis,
aktivitas dan kualitas hidup berkurang akibat ketidakmampuan baik fisik
maupun psikis yang sangat terganggu.

2. , her skin looks more 'saggy'/slacker, especially around the eyes

There are two main processes that induce skin aging: intrinsic and extrinsic. Extrinsic aging is
caused by environmental factors such as sun exposure, air pollution, smoking, and poor
nutrition. Intrinsic aging reflects the genetic background and depends on time. Extrinsically aged
skin is characterized by photo damage as wrinkles, pigmented lesions, patchy
hypopigmentations, and actinic keratoses

The involutional changes here mirror similar changes

occurring throughout the face and extremities. Gradual
tissue atrophy as the mesodermal content of the body begins
to shrink; the envelope of the ectoderm becomes too large,
and redundant skin folds and wrinkles appear. Loss of
adnexal structural support of tarsus, canthal tendons, and
orbicularis muscle with thinned skin leads to orbital fat
prolapse, eyelid malposition, blepharoptosis, and tearing.
In the lower eyelid, horizontal lid laxity is common. It can
be determined by the pinch test, which is the amount the
eyelids can be pinched away from the globe and the relative
delay and the absence of snap in the lids ability to regain its
normal anatomical position. Reduction in the orbital fat with
ageing causes the eyes to ‘‘sink in’’ accentuating the lid
laxity. Progressive laxity can result in punctual eversion and
later eversion of the eyelid margin from the globe (ectropion)
and subsequent symptoms of a watery eye. Generalised
descent of all of the mid-face because of ageing further
contributes to ectropion formation. If the pretarsal orbicularis
muscle is comparatively strong, the eyelid may undergo
inversion (entropion) instead causing eyelashes to rub
against the cornea and subsequent discomfort. Oculoplastic
surgeons operate symptomatic ectropion or entropion. These
conditions may also be operated upon before a cataract
 operation to avoid infection. In entropion, temporary relief
may be achieved by simply taping the lid to pull it outwards.
In the upper lids, the disinsertion or attenuation of the
levator muscle may cause involutional ptosis.
Age related
descent of the brow (brow ptosis) also contributes to the
ptosis formation. Excess upper eyelid skin along with anterior
migration of the preaponeurotic fat pads results in derma-
tochalasis or pseudoptosis. These are operated upon if they
are interfering visually.
Deepening of the lines of expression especially at the
lateral lid margins cause ‘‘crow’s feet’’, which are sometimes
relieved cosmetically by botulinum toxin injections, although
not on the NHS in UK.
Watery eye in the elderly, although mainly caused by eyelid
malposition, can sometimes result from true lacrimal
obstruction. If the nasolacrimal duct obstruction
causes
distressful watering or recurrent infections it can be treated
by dacryocystorhinostomy. The other end of the spectrum is
reduction in the amount of tears produced by the lacrimal
gland causing dry eyes. This is treated with artificial tears or
punctual plugs to retain tears in the conjunctival sac.

3. She has lost her weight, so that her body shape seems smaller
The pathophysiology of unintentional weight loss is poorly understood. Multiple studies have
looked at inflammatory cytokines such as tumor necrosis factor α, interleukin-1β, and
interleukin-6, and gut hormones such as cholecystokinin, glucagon-like peptide, and ghrelin.8
Elevated concentrations of tumor necrosis factor α have been associated with weight loss. It is
unclear whether this relationship is a direct cause or a marker for an underlying condition.9
Body composition changes with age. Lean body mass begins to decrease up to 0.7 lb (0.3 kg) per
year in the third decade. This loss is offset by gains in fat mass that continue until 65 to 70 years
of age. Total body weight usually peaks at 60 years of age with small decreases of 0.2 to 0.4 lb
(0.1 to 0.2 kg) per year after 70 years of age. Therefore, substantial weight changes should not
be attributed to normal anorexia of aging.10
In community-dwelling older adults, the causes of unintentional weight loss can be classified as
organic or psychosocial. Multiple studies, prospective and retrospective and in inpatient and
outpatient settings, have demonstrated that the most common etiologies are malignancy (19%
to 36%), nonmalignant gastrointestinal disease (9% to 19%), and psychiatric conditions such as
depression and dementia (9% to 24%). Overall, nonmalignant diseases are more common than
malignancy.1,11–16
4. She suffers blurred vision, hearing loss, easy to fall, especially from sitting to standing
The corneal endothelium cannot regenerate and hence the
endothelial cell density reduces with increasing age. The
remaining endothelial cells enlarge to cover the loss of some
of the endothelial cells with ageing resulting in pleomorph-
ism. As the endothelial cells maintain the corneal deturge-
cence, a further decrease in endothelial cell count beyond a
certain amount either because of surgical damage or
progressive guttata in Fuchs endothelial degeneration, can
result in corneal thickening and subsequent opacity and
decrease in quality of vision. If visual acuity is reduced
penetrating keratoplasty is considered

The process of aging contributes to visual loss through the deterioration of function of the eye
tissues and increased incidence of ocular pathology in the elderly2. The process of pathology
takes place over months to
Age Related Visual Impairment in the Elderly
This article was accepted: 16 August 2004 Corresponding Author: K Y Loh, Department of Family
Medicine, International Medical University Malaysia, Jalan Rasah, 70300 Seremban, Negeri
Sembilan
K Y Loh, MMed(Fam Med)*, J Ogle, FRCSEd(Ophth)**
*Department of Family Medicine, **Department of Ophthalmology, International Medical
University Malaysia, Seremban, Negeri Sembilan, Malaysia
Summary Visual impairment among the elderly is a major health problem. With advancing age,
the normal function of eye tissues decreases and there is an increased incidence of ocular
pathology. Demographic studies have shown that age is the best predictor of blindness and
visual impairment. The most common causes of age related visual impairment in the elderly are
presbyopia, cataracts, age related macular degeneration, primary open angle glaucoma and
diabetic retinopathy. Untreated visual impairment leads to physical handicap, increased
incidence of fall, depression, social isolation and dependency. Active screening for visual loss in
the elderly should be part of the health examination. The elderly should be encouraged to come
for formal 1-2 yearly eye assessment for early detection of visual impairment and to treat all
associated problems in order to prevent permanent visual loss.
years and patients usually have minimal symptoms initially. The 5 major causes of visual
impairment in the elderly are presbyopia, age-related cataracts, agerelated macular
degeneration, primary open angle glaucoma and diabetic retinopathy2,3.

 Pendengaran menurun

Ujung tangkai maleus melekat di bagian tengah membran timpani dan tempat perlekatan
ini secara konstan akan tertarik oleh muskulus membran timpani yg mnybbkn membran
timpani tetap tegang.Keadaan ini mnybbkn getaran pada setiap bagian membran timpani
 akan dikirim ke tulang2 pendengaran,dan hal ini tdk akan terjadi bila membran tersebut
longgar.

Guyton&Hall.Buku Ajar Fisiologi.2007.EGC:Jakarta

 Salah satu masalah utama seorang lansia sering mudah jatuh disebabkan faktor intrinsik:
gangguan gaya berjalan, kelemahan otot-otot kaki, kekakuan sendi, sinkop/ hilang
kesadaran sejenak dan dizziness atau goyang, atau faktor ekstrinsik yang menjadi
penyebabnya: lantai yang licin dan tidak rata, tersandung benda-benda, cahaya kurang
terang sehingga terganggu penglihatannya, dan sebagainya (Setianto,2000).
 Keseimbangan bekerja karena otak, otot dan tulang bekerja bersama untuk
mempertahankan keseimbangan tubuh dan menjaga seseorang dari jatuh baik ketika jalan,
bangkit dari duduk atau naik tangga. Sistem skeletal yang mempengaruhi keseimbangan
yaitu kekuatan otot, daya tahan dan kelenturan, yang memungkinkan otot untuk bergerak
secara sinergis. Otot-otot mengalami atrofi akibat berkurangnya aktifitas, juga seringkali
mengakibatkan gangguan metabolic atau denervasi saraf. Otot-otot sekitar sendi bekerja
ketika mempertahankan keseimbangan dan selanjutnya strategi postural akan digunakan
untuk mencapai keseimbangan (Bougie, 2001).
Dalam kesimbangan postural terdapat komponen yang saling berinteraksi yakni
1) Sistem sensoris, Penurunan fungsi sensoris pada lansia akan mengakibatkan gangguan
penerimaan informasi dari receptor sensoris (utrikuluskeseimbangan saat berbaring ; sakulus
keseimbangan saat berdiri ; disebut makulus), sehingga mengakibatkan penurunan kontrol
motorik.
2) Central processing,Terjadi penurunan daya hantar saraf 20-30 msec pada susunan saraf
pusat,yang mengakibatkan lansia lamban dalam mengantisipasi perubahan persepsi sensoris dan
respon motorik.
3) Sistem effektor, Pada sistem muskoloskeletal akan terjadi kekakuan sendi, penurunan lingkup
gerak sendi, penurunan kekuatan otot, daya tahan, kelenturan, dan perubahan garis postur. Tugas
utama dari sistem efektor adalah mempertahankan pusat gravitasi tubuh/Center Of Gravitation
(COG). Dimana tugasnya meliputi duduk,berdiri, atau berjalan ( Gucione, 2000).
 Salah satu bentuk aplikasi fungsional dari gerak tubuh adalah pola jalan. Keseimbangan,
kekuatan, dan fleksibilitas diperlukan untuk mempertahankan postur yang baik pada setiap
 individu (Pudjiastuti, 2003).Tidak fleksibelnya otot pada lansia dapat mengakibatkan
terbatasnya Lingkup Gerak Sendi (LGS) / Range of movement (ROM) diakibatkan
oleh adanya kekakuan otot dan tendon sehingga menyebabkan kontraktur
sendi.Menurut American Geriatric Society (AGS) tahun 2001 keseimbangan tergantung
pada sensasi, kekuatan otot, fleksibilitas, serta lingkup gerak suatu persendian.Penurunan
lingkup gerak sendi (LGS) dari ankle ke arah dorsal fleksi dapat mengganggu
keseimbangan berjalan dan sering dihubungkan dengan kejadian jatuh pada lansia
(Johnson et al., 2007).

5. She feels so dizzy and imbalance ( sama kyk no 4)

6. . She also hasn’t got her period since 5 years ago

Sistem Endokrin.

 Produksi semua hormon menurun.

 Menurunnya aktivitas tyroid, menurunnya BMR (Basal Metabolic Rate), dan menurunnya
daya pertukaran zat.
 Menurunnya produksi aldosteron.
 Menurunya sekresi hormon kelamin misalnya, progesteron, estrogen, dan testosteron.

7. the aging process resulted from various factors that involving many theories

1. ros
During skin aging the effectiveness of endogenous antioxidant system is diminished [17] and
ROS formation causes mainly DNA damage [18]. Oxidative stress due to aging process not only
induces DNA damage, but also, intracellular lipid peroxidation, abnormal protein oxidation
reactions, all of which result in cell damage [19], inflammation [20] [21], immune suppression
[21], oxidative stress, hyperplastic responses in skin as well as perturbed hormonal balances
[22], and premature skin aging [19]. The biological consequences of damage caused by stress
oxidative and consequently in DNA damage are alteration in gene expression and consequently
protein expression can be modified [20], blockage in RNA transcription [23], increased cell
death, altered metabolic redox balance [24] [25], and defects on transcription through RNA
polymerases I and II can occur [26]. The mechanism that can to explain the DNA damage in skin
aging due oxidative stress is the potentially result in a blockage in DNA synthesis, as replicative
DNA polymerases do not have the capacity to use damaged templates. This important blockage
may lead to the collapse of the replication fork, production of double-strand breaks, and,
ultimately, cell death [27]. These lesions, if not repaired in a timely manner, can cause severe
structural distortions in the DNA molecule, thereby affecting important cellular processes such
as DNA replication and transcription, and compromising cellular viability and functional integrity
[28]. DNA damage can also change the proteins turnover because of the alterations in the DNA
replication and transcriptions already related above. And for healthy and youth skin is necessary
basement membrane (BM) be intact and functional to maintain normal protein synthesis. Some
cosmetic ingredients also promote BM repair by increasing the synthesis of BM components,
such as laminin 332, and type IV and VII collagens, in the epidermis and/or the dermis. Hence,
BM represents a good target for skin-care products; components that enhance BM repair may
improve epidermal-dermal communication and skin homeostasis, thereby strengthening
defenses against “skin aging
2. Mitochondria are producers and also targets of oxidative stress, forming the basis for the
Mitochondrial Theory of Aging. Within the mitochondria an accumulation of somatic
mitochondrial DNA mutations induced by exposure to ROS, which leads to errors in
encoding polypeptides by mitochondrial DNA and the subsequent transfer activity and
oxidative phosphorylation is defective occurs. Over the years, the activity of the
mitochondrial respiratory system and its constituent enzymes such as cytochrome c oxidase
in a range of tissues including skeletal muscle, heart and liver decreases, and therefore the
integrity of the mitochondrial DNA is also reduced in these tissues [33] [34]. In the aging
process, accumulation of mutations in mitochondrial DNA, decreased oxidative
phosphorylation occurs as well as an imbalance in the expression of antioxidant enzymes
results in greater overproduction of ROS. Mitochondrial dysfunction and ROS production
leads to a vicious cycle which is the basis of mitochondrial free radical theory of aging.
Moreover, several lines of evidence have recently emerged to show that ROS play a crucial
role in the regulation of cell metabolism, antioxidant defense and post-translational
modification of proteins. Some authors point out that there are positive roles and
integrators mild oxidative stress caused by the mitochondria in the regulation of adaptation
in anti-aging and cleansing way beyond their roles in the vicious cycle of mitochondrial
dysfunction caused the aging process
3. Telomeres are DNA-protein complexes that cap chromosomal ends, promoting chromosome
stability. Telomerase is a ribonucleoprotein complex with a direct telomere protective
function. Telomere shortening re- presents lifetime exposure to oxidative stress and is
negatively correlated with age, smoking, and mortality. Smoking increases oxidative DNA
modification and thus may influence telomere dynamics and human telomerase reverse
transcriptase (hTERT) activity [54]. Telomere length is a molecular marker of cell aging, and
genomic instability due to telomere shortening has been linked to several aging-related
diseases. It was suggest that telomere length in human dermal fibroblasts can be shortened
by a single high dosage of UVA radiation, and that acute photodamage might contribute to
early photoaging in human skin via rapid telomere shortening [55]. How it was discussed in
previous sessions, elevation in ROS and dysfunctional mitochondria are closely associated
with senescence cells. And the aging of organisms is characterized by a gradual functional
decline of all organ systems. Mammalian somatic cells in culture display a limited
proliferative life span, at the end of which they undergo an irreversible cell cycle arrest
known as replicative senescence. Whether cellular senescence contributes to organismal
aging has been controversial. Herbig and coworkers (2006) investigated telomere
dysfunction, a recently discovered biomarker of cellular senescence, and found that the
number of senescent fibroblasts increases exponentially in the skin of aging baboons,
 reaching >15% of all cells in very old individuals. In addition, the same cells contain activated
ataxia-telangiectasia mutated kinase and heterochromatinized nuclei, confirming their
senescent status [56].
4. Infl ammation hypothesis of aging Even if the involvement of the infl ammatory process in
several (sub)clinical conditions (eg, atherosclerosis, diabetes, dementia) is well-
demonstrated, the importance of infl ammation in the aging process was recognized only
recently (McGeer and McGeer 1999; Chung et al 2001). Nevertheless, infl ammation is
growingly considered as a cornerstone of the mechanisms underlying the aging process, so
to even generate the neologism “infl amm-aging” (Franceschi et al 2000a). Infl ammation is
a complex host’s normal defense reaction to physiological and nonphysiological stressors.
Acute as well as chronic infl ammatory responses are constituted by sequential phases,
controlled by humoral and cellular stimula: 1) intracellular activation; 2) proinfl ammatory
cells in the tissues; 3) increase of vascular permeability; 4) damaging of tissues and cell
death (Huerre and Gounon 1996; Chung et al 2001). An individual threshold of the capability
to cope with stress has been hypothesized. If the age-related infl ammation (or infl amm-
aging) trespasses this level, the transition between successful and unsuccesful aging occurs.
Epidemiologic data support the hypothesis that the period of life during unsuccessful aging
(disability) is maximal in the elderly, and minimal in young people and centenarians
(Franceschi et al 2000a). Even when debating about infl ammation and its relationship with
aging, it is important to underline how this mechanism is associated with others at the basis
of different theories of aging. In fact, the close relationship between infl ammation and
oxidative damage is well-known in literature (Cesari et al 2005). In fact, reactive oxygen
species and reactive nitrogen species are heavily implicated in the infl ammatory processes.
The overproduction or uncontrolled release of reactive species is a major causative factor in
tissue infl ammation.
5. Immune theory of aging In 1989, Franceschi proposed the immune theory of aging, or
network theory of aging (Franceschi 1989; Franceschi et al 2000a), in which suggested that
aging is indirectly controlled by a network of cellular and molecular defense mechanisms.
The major parts of the network are constituted by DNA repair enzymes, activation of poly
(ADP-ribosyl) polymerase, enzymatic and nonenzymatic antioxidant systems (eg, superoxide
dismutase, catalase, glutathione peroxidase), production of
6. heat shock proteins (Franceschi 1989; Franceschi et al 2000b). These mechanisms function
to limit the negative effects of a variety of physical, chemical, and biological stressors. The
effi ciency of the network is genetically controlled and differs among species and individuals,
explaining in this way the observed differences in life span. In the network theory of aging,
the immune system represents the most powerful mechanism to face stressors (Franceschi
et al 2000a). In particular, Franceschi identifi ed the macrophage as the primary modulator
of the vicious cycle existing between innate immunity, infl ammation and stress. The
macrophage activation due to chronic stress may provide a potential explanation to the
subclinical chronic infl ammatory status characterizing older persons and, at the same time,
a possible feature of the aging process. Lymphocytes are also affected by the continuous
age-related antigenic stress, resulting in a chronic stimulation responsible for the expansion
of memory cells, the decrease (even exhaustion) of naïve cells, and the shrinkage of the T-
cell repertoire. Supporting this hypothesis and the importance of the immune system in
 determining the senescence is the evidence of the high incidence of tumors and greater
susceptibility to infections from pathogens shown by the older persons. It has been
suggested that aged subjects maintaining their immune functions at an exceptionally high
level are more likely to have a long life span (Wayne et al 1990; Pawelek et al 1999). As
noted above, theories of aging often overlap each other, suggesting interactions across
different systems and mechanisms. In this context it should be considered the association
between the immune cell functions (such as those involved in the cytotoxic activity and
particularly in phagocytes as regards their microbicidal activity) and the reactive oxygen
species generation. The excessive amount of reactive oxygen species not counteracted by
the antioxidant defenses can become a potential source of tissue damage (De La Fuente
2002). Moreover, antioxidants maintain the integrity and function of membrane lipids,
cellular proteins, and nucleic acids and the control of signal transduction of gene expression
in immune cells. Not surprisingly, immune system cells usually contain higher
concentrations of antioxidants than do other cells (Knight 2000), given the high percentage
of polyunsatured fatty acids in their plasma membranes. Thus, the immune cell functions
are strongly influenced by the antioxidant/ oxidant balance and, therefore, the antioxidant
levels play a pivotal role in maintaining immune cells I) in a reduced environment and II) in
protecting them from oxidative stress, so to preserve their adequate functioning (Knight
2000).
7. Neuroendocrine theory of aging It is generally accepted a bidirectional communication
between the nervous and the immune systems (Besedovsky and Del Rey 1996). With aging
not only a functional decline in the immune and nervous systems occurs, but also an
impaired relationship between these two regulatory systems can become evident, with the
resulting loss of homeostasis and higher risk of death (Fabris 1991; De La Fuente 2002). The
neuroendocrine theory proposes that aging is due to changes in neural and endocrine
functions that are crucial for:1) coordination and responsiveness of different systems to the
external environment; 2) programming physiological responses to environmental stimuli;
and 3) the maintenance of an optimal functional status for reproduction and survival. These
changes, not only selectively affect neurons and hormones regulating evolutionarily signifi
cant functions such as reproduction, growth, and development, but also infl uence the
regulation of survival through adaptation to stress. Thus, the life span, regulated by
“biological clocks”, would undergo a continuum of sequential stages driven by nervous and
endocrine signals. Alterations of the biological clock (eg, reduced responsiveness to the
stimuli regulating the clock, excessive or insuffi cient coordination of responses) would
disrupt the clock and the corresponding adjustments (Finkel 1976; Timiras 1978; Weinert
and Timiras 2003). An important component of this theory indicates the hypothalamo-
pituitary-adrenal (HPA) axis as the primary regulator, a sort of pacemaker signaling the
onset and termination of each stage of life. The HPA axis controls the physiological
adjustments aimed at the preservation and maintenance of an internal homeostasis despite
the continuing changes in the environment (Weinert and Timiras 2003). During life span,
chronic exposure to severe and multiple physical, biological, or emotional stressors may
exhaust or weaken this capacity to adapt and to the so-called “disease of adaptation” and
death (Selye 1976; Weinert and Timiras 2003). Aging should then be considered as the result
of a decrease ability to survive stress, suggesting once more the close relationship between
 stress and longevity. The integration of responses to environmental stimuli seems to be
carried out by hypothalamus from information derived in various cerebral structures. The
hypothalamus itself regulates: 1) nervous functions (eg, sympathetic and parasympathetic
visceral functions), 2) behaviors (eg, sexual and eating behavior, rage, fear), and 3)
endocrine functions
(eg, production and secretion of hypophysiotropic hormones stimulating/inhibiting hormone
release from the hypophysis). In response to hypothalamic signals, the hypophysis produces and
secrets several hormones acting in the regulation of many important functions of the body. This
regulation is controlled by the release of hormones (eg, growth hormone, oxytocin, vasopressin)
or by the stimulation of peripheral endocrine glands (eg, adrenal cortex, thyroid, gonads). Major
hormones of the adrenal medulla are the catecolamines epinephrine and norepinephrine,
functioning as neurotransmitters for the sympathetic division of the autonomic nervous system
and rapidly responding to any external or internal stress through circulatory and metabolic
adjustments (Weinert and Timiras 2003). With aging, a reduction in sympathetic responsiveness
is characterized by: 1) a lower number of catecholamine receptors in peripheral target tissues;
2) a decline of heat shock proteins that increase stress resistance; and 3) a decreased capability
of catecholamines to induce heat shock proteins. The hormones of the adrenal cortex are
glucocorticoids (responsible for the regulation of lipid, protein, and carbohydrate metabolism),
mineralcorticoids (regulating water and electrolytes), and sex hormones. Among the latter is
dehydroepiandrosterone, which has shown to decrease with aging. Dehydroepiandrosterone
replacement therapy has been advocated in humans, despite unconvincing results (Daynes and
Araneo 1992). Glucocorticoids, as well as other steroid hormones, are regulated by positive and
negative feedbacks between the target hormones and their central control by the hypophysis
and hypothalamus. With aging and in response to chronic stress, not only feedback mechanisms
may be altered, but also glucocorticoids themselves become toxic to neural cells, thus disrupting
feedback control and hormonal cyclicity (Sapolsky et al 1986; Sapolsky 1992; Weinert and
Timiras 2003). The circulating levels of growth hormone, testosterone, estrogen,
dehydroepiandrosterone, and other hormones decrease with age. Although some hormone
replacement strategies have been shown in clinical trials to modify some of physiological
attributes associated with aging, negative side effects occur frequently with those interventions
shown to have some benefi t, such as growth hormone. Although the epidemiological data are
overwhelmingly positive regarding some health benefi ts of estrogen replacement therapy, a
recent study has raised a concern about ovarian cancer after long-term use. It has been shown
that melatonin supplementation increases the mean life expectancy of mice by approximately
5%, but in association with an increase in spontaneous tumor incidence. In order to adequately
address hormone decline occurring with aging, it is crucial the understanding of the complex
hormonal cascade, an intricate interplay between signals, pathways, and production and
delivery systems. Estrogen replacement therapy represents a special case of hormone
replacement therapy and deserves particular attention because of its long clinical history and
apparent record of success in increasing quality of life in postmenopausal women. Estrogen is
particularly recommended for the prevention of osteoporosis, but it has been suggested it may
reduce the risk of dementia and cardiovascular disease. It has been estimated that favorable
changes in plasma lipids may account for approximately 25% of the cardioprotective effect of
estrogen. The conclusion that estrogen protects postmenopausal women against cardiovascular
disease is now being questioned, based mainly on experiments examining secondary prevention
in women with preexisting heart disease. Estrogen replacement therapy has been called the fi
rst true anti-aging therapy. However, no results have yet been reported of randomized studies
that compare effects of this therapy with placebos, beginning at the menopausal transition, in
women with no known preexisting coronary heart disease or dementia. It has been
demonstrated that circulating levels of growth hormone drop with increasing age. It has also
been shown that GH replacement in adults with pituitary disease and GH defi ciency has benefi
cial effects on body composition, reducing fat and increasing lean body mass, muscle strength,
and bone mass. Rudman and colleagues investigated whether GH injections in older men would
restore muscle mass typical of younger men. They found that insulin growth factor (IGF)-1 levels
did rise and that lean body mass increased while fat mass decreased, suggesting that GH
injections did reverse the changes in body composition that were due to age and
deconditioning. Recent data obtained with mice suggest that lifelong overproduction of GH
reduces longevity in mice, whereas underproduction or an inability to respond to GH increases
it. Transgenic mice overexpressing GH exhibit severe kidney lesions and increased incidence of
neoplasms, and overproduction of GH in adult humans leads to a condition known as
acromegaly, which is characterized by excessive growth of certain organs and tissues, but also
premature heart and lung failure.
The evidence from both nematodes and fruit flies suggests that decreased activity of the insulin-
like signaling pathway is associated with increased life expectancy, rather than the reverse.
Thus, further research is needed before the GH supplementation in humans encouraged by
many “antiaging” clinicians can be considered either safe or useful for long-term intervention.
8. Caloric restriction A single chapter in this review is deserved by caloric restriction, the only
nongenetic intervention that has consistently shown to slow the intrinsic rate of aging in
mammals (Dirks and Leeuwenburgh 2006). It is defi ned by the reduction in caloric intake while
maintaining essential nutrient requirements. Traditionally, experimental mammalian models of
caloric restriction reduce caloric intake by ~40% of the adlibitum diet throughout the lifespan of
the animal. This reduction has resulted in a 30%–40% increase in maximum lifespan (Weindruch
et al 1986). How is caloric restriction able to increase lifespan? It is likely that this intervention
can obtain benefi cial effects by acting at various levels of function and involving a number of
molecular cellular, and systemic changes. Not only is longevity increased, but also metabolic (eg,
increased tissue sensitivity to insulin), neuroendocrine and immune (eg, increased defenses
against stress, infections, cancer), and collagen responses (eg, reduction of cross-linking) are
signifi cantly enhanced (Mobbs et al 2001). It is noteworthy that such functional changes might
also be modulated by changes in gene expression profi le. Caloric restriction may promote
longevity by a metabolic reprogramming with a transcriptional shift (perhaps triggered by
insulin) toward 1) reduced energy metabolism, and 2) increased biosynthesis and turnover of
proteins. It has also been demonstrated that caloric restriction markedly infl uences the
expression of pathological phenotypes in rodent species selectively bred as models of human
pathology (Weinert and Timiras 2003). Even if the short-term effects in humans are promising
(Walford et al 1999; Weyer et al 2000; Fontana et al 2004), long-term studies are not
surprisingly diffi cult to conduct in humans. The lack of data from human models is mainly due
to the diffi culties of adhering to this rigorous intervention and the length of the human life
span. The most famous reports about the effects of caloric restriction on humans’ health were
 obtained from the Biosphere 2 experiments. Biosphere 2 is a closed ecological space located in
the deserts of Arizona. In 1991, eight individuals entered the biosphere for a two-year period to
study the effects from living in a closed system. Because of unexpected technical problems, the
access to food was limited for the entire duration of the study, so that the actual caloric intake
of the participants was approximately 30% lower than what expected. Physiological and
biochemical measurements were
assessed over the time spent inside the biosphere (ie, while crew members experienced caloric
restriction) as well as 18 months after exiting the biosphere and returning to their normal diets.
The physiological modifi cations experienced by the Biosphere 2 participants were similar to
those found in caloric restricted rodents and nonhuman primates: decline in metabolic rate,
body temperature, and systolic and diastolic blood pressure, and reductions in blood glucose,
insulin, and thyroid hormone levels. It has been shown that the Okinawan population is
characterized by reduced morbidity and mortality, and the greatest percentage of centenarians
in the world lives in this island. It has been hypothesized that the long disability-free life
expectancy of this population might be due to the diet, based on vegetables, grains, soy, fruits, fi
sh and seaweed, and characterized by a low caloric intake (~20% less than the rest of Japan and
~40% less than United States). It is noteworthy that this diet is very similar to the caloric
restriction interventions designed for experiments in animal models. Despite of the abundant
data showing health benefi ts and the reduction of the aging rate by use of a caloric restriction
intervention in mammalian animal models, it is likely that these benefi cial effects will be lost in
the translation to human models (Dirks and Leeuwenburgh 2006). Consequently, the previous
great expectations about long-term caloric restriction in humans as the new “fountain of youth”
have recently been resized.
8. adopting a healthy lifestyle & keeping her social life good.