Immune ageing in health and disease

Immune-ageing
Aging of the immune system has been associated with failing immune responses
directed to new pathogens or tumour antigens [1]. Conversely, an overactive
immune system is thought responsible for the development of cardiovascular
disease and auto-immunity (e.g. rheumatoid arthritis, giant cell arteritis and
polymyalgia rheumatica) [2].
Of the leukocyte subsets, T lymphocytes seem to be most influenced by
aging due to the gradual loss of their specific maturation organ, the thymus
[3]. Besides thymic involution, immune senescence may result from: 1) shrinkage
of the T cell repertoire through continuous antigen stimulation favouring the
development of functionally altered, oligoclonal, senescent T cells (identified
by CD28/CD27 loss and telomeric erosion) and 2) a chronic low degree of
inflammation (termed inflamm-ageing) evidenced by increased serum levels of
inflammatory cytokines and acute phase proteins [2,4,5]. Longitudinal studies
(that included healthy octo-, nono- and centenarians) have identified a so
called immune risk phenotype (IRP) that is associated with poor immune function
and increased mortality risk: a CD4+/CD8+ T cell ratio < 1, low CD19+ B cell
counts and a poor lymphocyte proliferative response [6,7].
Besides senescent T cells, other subsets of CD4+ and CD8+ T cells have
been described (table 1). Historically, CD4+ T cells were divided into T helper
1 cells and T helper 2 cells. More recently Th17 and regulatory T cells were
identified. Similar to CD4+ T cells, CD8+ T cells can be divided into three
subsets (T cytotoxic 1, 2 and 3) based on IFN-gamma, IL-4 and IL-17 production.
However, little is known about whether these cell subsets alter during healthy
versus unhealthy ageing.

Health status: SENIEUR protocol
To study age-related changes of the immune system, it is important to recruit
elderly donors who are truly healthy. Many elderly people have diseases or
drugs that influence the immune system. In order to study the effect of ageing
(instead of disease) on the immune system, the SENIEUR protocol has been
developed [8]. This protocol encompasses careful history taking, physical
examination and a series of mandatory blood and urine tests. Using this method
for recruitment of healthy elderly individuals in immunological studies is
important, as it allows differentiation of healthy ageing (SENIEURs) from
less-/non-healthy ageing (non-SENIEURs) [8]. The SENIEUR protocol has been
further validated in other studies, and is currently regarded as the best
protocol to assess health status of elderly individuals in a standardized way
[9,10].

Frailty
As stated, elderly people are more susceptible to infections, autoimmunity and
cancer. This general age-associated susceptibility to diseases in elderly
people is currently known as *frailty*. The concept of frailty is important, as
it recognizes that in elderly populations a wide individual disparity is
present regarding morbidity and mortality risks. Notably, these risks cannot be
entirely explained by chronological age, as some 60 year old persons are more
frail when compared to some 90 year old persons [11].
Various instruments have been devised to identify frail elderly people.
Early instruments to measure frailty were the protocol of Fried et al. and the
Groningen Frailty Indicator (GFI) [11,12]. The Fried protocol mainly focuses on
physical components of functioning in the elderly, such as grip strength and
gait speed. In contrast, the GFI relies more heavily on psychosocial components
of functioning. To date, the Fried protocol is the most widely used instrument
internationnaly to assess frailty, and has been shown to predict mortality in
cohorts of elderly people [13]. In addition to the GFI (mainly used in the
UMCG), the Tilburg Frailty Indicator (TFI) has been developed. The TFI is a
modification of the GFI, and has been more extensively validated compared to
the GFI [14,15]. The Fried protocol and the TFI represent two different models
of frailty and they measure different modalities. The Fried protocol measures
fysical strength whereas the TFI, which is a questionnaire, measures
psychological and social functioning.
So far, it remains unclear whether the adaptive immune system of frail
elderly people differs from that in non-frail elderly people.

Primary Objective: To study changes of T cell subsets (Th1/Tc1, Th2/Tc2,
Th17/Tc17, regulatory T cells and senescent T cells) in healthy ageing and
unhealthy ageing.

Secondary Objective(s):
- To study the immune risk phenotype in healthy persons versus frail and
diseased persons.
- To study T cell function in healthy persons versus frail and diseased persons.
- To assess the construct validity of the Groningen Frailty Indicator to more
extensively validated measures of frailty (Fried and TFI)

Observational study with determination of health status, frailty status and T
cell subsets and cytokines in peripheral blood.

Donors from the different age groups/elderly groups will gain no direct benefit
from the study. In times of rising age expectancies and demographic shifts
towards older populations, we believe that more insights in the role of the
immune system in the ageing process, will be useful to develop healthy ageing
strategies in the future.
In addition, we hope to better understand which changes occur in the (adaptive)
immune system with ageing, and which of these changes are associated with poor
health (SENIEUR status) or frailty (Fried, TFI, GFI) later in life.
We do not expect that questionnaires and venapuncture will put study
participants at risk.