Immunosenescence and Elderly Frailty
The ongoing pandemic of COVID-19, caused by the severe acute respiratory syndrome
coronavirus (SARS-CoV-2), has dramatically shown how the elderly are fragile in spite
of advancement in healthcare and medical attention in Western countries (1). With
the global growth of the elderly population, the burden of noncommunicable diseases,
including heart disease, cancers, metabolic, neurologic and autoimmune diseases, as
well as infectious diseases is projected to dramatically increase, thus imposing critical
public health challenges and demanding multidisciplinary efforts to develop more effective
preventive and therapeutic strategies. Lying along the causal path between aging and
negative health outcomes, a progressive functional decline of the innate and adaptive
immunity (immunosenescence) occurs with age, which leads to increased risk for infectious
diseases and ineffective response to vaccination, as well as for other non-infectious
immune-related chronic degenerative diseases (2).
The unsuccessful immune response to SARS-CoV-2 has been associated with a dysfunctional
innate immune response, while neutralizing antibody response by adaptive immunity
correlates with beneficial outcomes (3). Aging is accompanied by a decline in the
production of naïve T cells and naive B cells, as a consequence of reduced thymic
output, bone marrow and lymph nodes function (4). Decreased proliferation and differentiation
of activated T and B cells also occur in lymph nodes with aging. Consequently, these
age-related changes in the number and function of effector cells impair the immune
responses to emerging infection, predisposing older adults to a higher risk of viral
and bacterial infections (5).
It has been increasingly shown that this immune dysfunction and associated frailty
are, to a relevant extent, accounted for by gender- and age-related changes in the
circadian system (6).
The Circadian System
Biological life is regulated by, and depends on, circadian clocks that allow homeostatic
daily rhythms in behavior, physiology, endocrinology and metabolism, with the sleep-wake
cycles alternation as the most directly experienced expression of this regulatory
system.
The circadian system regulates daily rhythms in sleep-wake, hunger-satiety, and body
temperature. Circadian clocks include the central pacemaker situated in the suprachiasmatic
nucleus in the brain, and peripheral clocks in various tissues (7). By receiving light
inputs via the retina, the suprachiasmatic nucleus is entrained to the 24-h day/night
cycle, and in turn synchronizes peripheral clocks. At the cellular level, molecular
clock components generate circadian fluctuation in basic cellular functions, e.g.,
gene expression, protein translation, and intracellular signaling, which are all involved
in fundamental processes including cell cycle regulation, nutrient sensing/utilization,
metabolism, stress response, redox regulation, detoxification, and cell defense (immunity
and inflammation) in a tissue-specific manner (8).
Gender and Age-Related Changes in Sleep
The cyclic occurrence of periods of non-rapid-eye-movement (NREM) sleep and rapid-eye-movement
(REM) sleep characterizes the organization of human sleep. Current evidence confirms
the presence of age-related changes in sleep duration and architecture, so that older
adults could have a reduced ability to sleep rather than a reduced sleep need (9).
Decreases in slow-wave sleep (SWS), slow waves (SW; <4 Hz and >75 μV) and slow-wave
activity (SWA; spectral power 0.5–4 Hz) represent one of the main age-related changes
in sleep. A factor modifying the impact of aging on sleep is gender. Indeed, women
present sharper and steeper SW compared with men. The production of flatter slopes
of SW rather than sudden SW slope (200 μV/s) is more frequently observed in older
man compared with older women (10). During young adulthood, women reach both puberty
and their peak eveningness more precociously compared with men. Sleep is longer in
duration in women than in men until age 50–60, that coincides with menopause. Core
body temperature and melatonin rhythms are phase advanced, and the intrinsic circadian
period is shorter in women compared with men (9). Sleep-endocrine activities also
exhibit gender differences and changes in nocturnal hormone secretion occur during
aging. The sleep-related secretion of different hormones (particularly neuropeptides
and steroids) shows distinct patterns, exerting specific effects on sleep (11): studies
in male and female rats found modifications in responses of anterior pituitary to
CRH, LHRH, TRH, and GHRH throughout the whole life span (12). Some hormones (GHRH,
ghrelin, galanin, NPY) positively regulate sleep, at least in males: GHRH promotes
NREM sleep, and stimulates GH. Other peptides (CRH, somatostatin) impair selective
NREM sleep: CRH contributes to wakefulness and to the HPA hormones. Notably, in women
GHRH induces CRH-like effects. Cortisol secretion is higher in normal young females
than in males, and contributes to REM sleep maintenance. Aging as well as some pathological
conditions such as depression are accompanied by modifications in the CRH:GHRH ratio
with an increase of CRH. In females the menopause is the crucial point for the occurrence
of impaired sleep, while in men the sleep quality gets worse steadily: different concurrent
decreases of SWS, SWA and GH secretion emerge already during the third decade of life
(11). These sleep age-related changes in sleep-endocrine activities, albeit different
in both male and females, can impair health and increase the risk for several diseases
and infections in elderly populations (13).
Inflammation, Sickness, and Sleep
Inflammation is a physiological response of the immune system to infection and injury
regulated by different immune cells and inflammatory factors. Inflammatory molecules
(cytokines, prostaglandins, and complement factors) act locally but also at a distance.
Locally, they take action on nearby immune cells to stimulate their recruitment/activation,
and on the vascular system to induce vasodilation and vascular permeability. They
also communicate over great distances to other organs, establishing a systemic inflammation
that can involve brain inflammation, also known as neuroinflammation (14). During
infections and injuries, peripheral cytokines can come into contact with the brain
via the humoral routes and the neural routes, working in parallel and synergistically
to cause neuroinflammation. A strategy to adaptively recover from infections and injuries
includes sickness, which induces an inflammatory response associated with physiological
and behavioral changes involving disturbed sleep. Evidence point to a reciprocal interactions
between sleep and immune function (13), where poor sleep alters immune function and
immune activation alters sleep. Inflammatory mechanisms, involving the pro-inflammatory
cytokines interleukin (IL) 1α, IL1β, IL6, interferon (IFN)α, IFNγ, tumor necrosis
factor (TNF)-α, and TNF-β, are induced by pathogen and are able to modulate sleep
organization and main sleep-wake behavior (15). Although IL-1 is commonly associated
with pathological states and plays critical roles in host defense, this cytokine is
also implicated in the regulation of physiological sleep (15, 16).
Immunosenescence, Sleep, and Frailty
With aging, the circadian indicators of the sleep-wake organization, i.e., sleep onset,
body core temperature, motor activity, and melatonin phase, have an earlier daytime
emergence (6); the circadian phase advances in parallel and the rhythms amplitude
is reduced while the period is shortened. Evidence from animal studies indicate that
the activity of the suprachiasmatic nuclei orchestrating the circadian rhythms is
decreased with aging and the clock gene expression is impaired (17, 18); the autonomic
nervous system cyclic organization also changes with age (6). In peripheral blood
cells, level of Bmal1 expression, a core clock gene and a regulator of innate immunity,
was shown to correlate inversely with age in women (19). Animal results further support
these age-associated changes in clock gene expression, but also suggest a causal role
for these changes in the aging process. For example, knockouts of the clock genes
Bmal1 and Period result in an accelerated aging in Drosophila and mice, characterized
by increased tissue decline, cognitive dysfunction, and shorter lifespan compared
with age-matched wild-type controls (6). On the other hand, the increased susceptibility
to respiratory viral diseases in winter may be associated with the seasonal variation
of Bmal1 expression, whose low levels in winter correlate with enhanced viral disease
(20).
One of the most consistent evidence of age-associated circadian disruption is the
age-associated changes in sleep, with its quantity progressively reducing (sleep deprivation)
and quality worsening from around 55 yrs. of age to become worst over 65 yrs. also
in subjects without major sleep disorders. Major sleep disorders and especially sleep
deprivation are associated to immune dysfunction and chronic inflammation and to higher
risks of infection and psychiatric, cerebral/cardiovascular, metabolic/hormonal co-morbidity
and related mortality irrespective of age, according to surveys and population-based
studies (21, 22). Congruently, the disruption of circadian rhythms results in comparable
outcomes and in the elderly adds and contribute to the cumulative decline in several
(brain, endocrine, immune, muscle) physiological systems during a lifetime.
The circadian system and sleep have emerged as important intertwined regulators of
immune defense (23, 24). Trafficking of immune cells and proinflammatory cytokines
are under circadian regulation and oscillate in accordance with the rest/activity
cycle (5, 25). Animal studies found that global, brain or peripheral knockout of clock
genes alters this circadian fluctuation and leads to exacerbated inflammatory response
to infection or other pathogenic stimuli, oxidative stress, and age-related phenotypes,
thus revealing a direct role for clock genes in suppressing chronic inflammation and
ensuring its timely resolution (26, 27).
Additionally, adequate sleep quantity and quality support the immune function, reduce
infectious risks and improve vaccination responses by regulating immunological memory
and humoral immunity (24). On the contrary, sleep deprivation is associated with chronic
inflammation, greater susceptibility to infection and worse clinical protection after
vaccines (24), as well as with increased risk for inflammatory diseases and total
mortality (22). Notably, both sleep-wake cycle and circadian clock components contribute
to maintain blood-brain barrier function, important for the neuroimmune system (28).
Furthermore, the circadian rhythmicity of gene expression related to immune function
and stress response, among others, is disrupted after sleep deprivation, as experimentally
demonstrated in humans (29), underscoring the interrelationship between sleep and
circadian system and their interface with health. Together, observational and experimental
data point to immune dysfunction and chronic, low-grade activation of inflammation
in connecting circadian disruption to negative health consequences in aging (Figure
1).
Figure 1
Schematic organization of the bidirectional relationship between central and peripheral
clock genes expression and their effects on circadian rhythms, i.e., sleep-wake cycle,
and on immunity. Infectious agent can interfere with both the expression of clock
genes and the activation of the immune system. Host susceptibility to an invading
pathogen modify during 24 h and with aging.
The spatiotemporal regulation of gene expression and associated functions contribute
to maintain physiology and behavior.
Future Directions: Therapeutic Opportunities Thinking About Age-Related Sleep Changes
From accumulating evidence new therapeutic opportunities have been generated for two
main reasons: first, by leveraging rhythmic aspects of some diseases in occurrence,
including cardiovascular or neurological ones (30) and infection disease also knowing
that the timing of virus infection during the day influences infection disease outcome
and this effect is found under different types of light–dark cycles (12-h light/12-h
darkness compared with 24-h darkness), and in genetic models of circadian disruption
(31); second, by optimizing timing of drug administration in order to increase its
efficacy and minimize adverse side effects (chronopharmacology) (32). Murine and human
studies have suggested that the efficacy of vaccination is under circadian control.
Animal studies show that the immune response to vaccination is improved when vaccination
is performed at the time of higher circadian expression of TLR9 (Toll-like receptor
9) (33). Likewise, a time dependance of the antibody response to viral challenge in
humans was also shown: morning vaccination against hepatitis A and influenza virus
increased the antibody response as compared to afternoon vaccination (34). The majority
of drugs approved by the FDA have targets showing circadian rhythm in expression and
functions (8), and the drug absorption, transportation, conversion and cell uptake
also show rhythmic expression. As a consequence, any strategies to improve drug efficacy
in the elderly should consider the impact of circadian rhythmicity on treatment efficacy.
Chronopharmacology can therefore constitute an additional factor of variability in
drug response in the elderly.
Conclusions
The relationship between aging and circadian disruption is bidirectional, with aging
associated with circadian dysfunction, and behavior and genetic disruption of the
circadian clock leading to aging-like phenotypes. The result is the establishing of
circular, self-sustaining mechanisms of dysregulation with potentially severe impact
on health. The bidirectional relationship among sleep/circadian rhythm and immunity
has received minor attention to date mainly if we consider the emergence of sleep
disorders in the adulthood that persist until the elderly. It remains unclear the
extent to which sleep disorders affect the immunosenescence in the later life. During
the lifetime, a progressive cumulative decline in physiological homeostasis occurs,
thus reducing the quality of life, and promoting isolation and adverse health outcome
in the elderly (35). In this subpopulation with combined motility and cognition impairment,
multimorbidity, sarcopenia and reduced autonomy (~7–12% in Western countries), the
misalignment between the circadian sleep-wake cycle and the daily activities further
reduces adaptation and can result in highest incidence of severe adverse medical or
traumatic events (36). By decreasing the amplitude in the rhythms of locomotor activity
and temperature, circadian rhythmicity could worsen motility, as recently demonstrated
in a mouse model of Bmal1 knockout (26).
The link among the disorders of circadian clock, sleep and immunosenescence qualify
today as a high-priority healthcare, welfare and social constraints with high estimated
direct and indirect costs, that hover higher in the elderly (36) if counterbalancing
behaviors or measures are not devised and widely represented in the medical practice.
The field of circadian rhythm has recently become a potential therapeutic target for
the treatment of diseases as we learned by infectious models, thus improving life
expectancy and quality of life of older persons.
The circadian pattern of the immune system contributes to shape the host ability to
respond to viral infections and the host–pathogen interaction. Viral infections and
other infectious diseases influence the host circadian clock drive. Therefore, in
the complex host–pathogen interaction a role of timing can be suggested, offering
new therapeutic opportunities based on chrono-modulated antiviral strategies. A more
in-depth research in the interrelationship of circadian system and immunity in the
elderly, with multidisciplinary competences, from (chrono)biology, (chrono)pharmacology,
neuroimmunology, sleep to integrative physiology, is advisable and possibly overdue.
Author Contributions
SG and WS conceived the manuscript. SG, EG, and PL wrote the manuscript. NB and WS
revised the manuscript. All authors contributed to the article and approved the submitted
version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.