Biogerontology (2015) 16:587–597

DOI 10.1007/s10522-015-9567-y

REVIEW ARTICLE

Genes and life-style factors in BELFAST nonagenarians:

Received: 20 January 2015 / Accepted: 4 March 2015 / Published online: 14 March 2015
Ó The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract Understanding how to ‘Age Longer and can help dissect out how to live not only longer but
Age Well’ is a priority for people personally, for better. Personal family history and narrative are
populations globally and for government policy. powerful tools that help to determine familial traits,
Nonagenarians are the oldest members of our societies beliefs and social behaviours and when used in parallel
and survivors of their generation. Approximately with new biotechnology methods inform and elaborate
10 % of nonagenarians reach 90 years and beyond in causality. Here we present themes and insights from
good condition and seem to have a combination of personal narrative enquiry from nonagenarian par-
both age-span and health-span. But what are the ticipants from the Belfast Elderly Longitudinal Free-
factors which help people reach their ninetieth birth- living Ageing STudy (BELFAST) about factors they
day and beyond in good condition? Are they genetics, consider important for good quality ageing and relate
as in ‘nature’, or do they depend on ‘nurture’ and are these insights to the emerging genetics and life-style
related to environment, or are both factors inextricably evidence associated with healthy longevity.
intertwined within the concept of behavioural genet-
ics? Nonagenarians have rich life experiences that can Keywords BELFAST nonagenarians
Genes

teach us much about ageing well; they are reservoirs of Life-style
Nurture
Nature
Narrative
genetic, life-style and behavioural information which

J. N. M. Rea Introduction
Research Department Primary Care and Population
Health, University College London, London, UK
Mixed method research, using both quantitative and
A. Carvalho
I. M. Rea (&) qualitative aspects, has the potential to ask contrasting
School of Medicine, Dentistry and Biomedical Science, and distinctive questions about the interface between
Queens University Belfast, Belfast, Northern Ireland, UK the scientific and social world, and to gain under-
e-mail: i.rea@qub.ac.uk
standing about how the evidence from biological and
S. E. McNerlan life sciences can be acted out in the real world of
Regional Cytogenetics Laboratory, Belfast Health and individual beliefs and behaviours. Those differ-
Social Care Trust, Belfast, Northern Ireland, UK ences—and relationships between the interdisci-
plinary fields of life sciences and those of social
H. D. Alexander
I. M. Rea
School of Biomedical Science, University of Ulster, science, arts and humanities—help to bring the
Coleraine, Northern Ireland, UK relevance of science into the socio-economic world

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of everyday life, because as a recent editorial in Nature was given by Research Ethics Committee Northern
argues ‘science doesn’t advance far if we don’t Ireland (ORECNI), 08/NIR03/42 and by The Queens
understand the dynamics of behaviour, attitude and University Belfast.
organisation’ (Editor 2015).
Present day social science is increasingly recognis-
ing the validity of the nonagenarian insights which are Nonagenarians narrative insights about their
telling us powerful messages about their ageing and longevity
are directly in line with present-day public health
campaigns-encouraging populations to adopt better Using grounded theory and qualitative analysis
lifestyles and behaviours in order to make for a (Glaser and Strauss 1967; Strauss and Corbin 1990),
healthier life course. five key findings and insights were identified by
Therefore in the BELFAST nonagenarian study, it nonagenarians themselves as important in their long
was of interest to identify what range of behaviours, lives and good quality health (Rea and Rea 2011; Rea
interventions and self-management strategies had Maeve 2013).
supported and contributed to the BELFAST ‘elite’ The five main themes were identified by BELFAST
nonagenarian’s combination of age-span and health- nonagenarians as important factors in their longevity
span, and which exemplified the Perl ‘escaper’ included (1) genes (2) diet (3) good health (4) physical
phenotype (Evert et al. 2003). Through narrative activity (5) social networks and resilience. Each will
enquiry, we aimed to get a sense of the nonagenarian be discussed briefly in the context of some of the
knowledge and engagement with their own good present day evidence relating to longevity.
quality ageing, in terms of life-style and behaviours.
Here we discuss the main themes which the
nonagenarian themselves identified as important Genes and longevity
pointers in their age-span and health-span, relate these
to some present day evidence about genes and life Apolipoprotein E gene (ApoE)
style interactions related to longevity and discuss how
the combined evidence supports everyone adopting Many nonagenarians considered that the genes within
better ageing strategies. their extended families were important factors con-
tributing to their long lives.
The ApoE gene is one of the most important and
Subjects and methods consistent genes identified with respect to both healthy
longevity and age-related disorders. Age-related dis-
In the BELFAST study, 90 year old subjects, who eases such as Alzheimers, and vascular dementia
were ‘very good’ for their age, also called ‘elite’ and (Corder et al. 1993; Licastro et al. 2007; Chuang et al.
met the Senieur protocol (Lightart et al. 1984), were 2010) and cardiovascular risk (Eichner et al. 2002;
recruited through their General Practitioners, from the Ilveskoski et al. 1999) have been regularly associated
Greater Belfast area. Subjects willing to enrol, were with the ApoE gene and particularly the ApoE4 allele
community-living, mobile, and mentally competent which tracks with higher lipoprotein values (Bennet
(mini mental score examination [ 26/30), (Folstein et al. 2007). In parallel studies ApoE has also been
et al. 1975) and gave written consent. Briefly, subjects identified as the single most important gene associated
gave blood samples for DNA and other laboratory with ‘healthy longevity’ in a host of individual studies
variables, responded to nutrition, life style and including locally in BELFAST nonagenarians (Ben-
medical history questionnaires, blood pressure and nati et al. 2010; Rea et al. 2001), several meta-analyses
anthropometric measurements (Rea et al. 2009) and and most recently in the European Genetics of Healthy
provided self-directed narrative life-stories (Ganze- Ageing (GeHA) nonagenarian sibling cohort where it
voort and Bouwer 2007) together with structured is closely related to the TOMM 40 gene location
questions (Rea and Rea 2011; Rea Maeve 2013). (Beekman et al. 2013; Deelan et al. 2011; Deelen et al.
Ethical permission for the Belfast Elderly Longitudi- 2014), which is mostly associated with the ApoE4
nal Free-Living Ageing STudy (BELFAST) studies variant (Brooks-Wilson 2013). Early research by

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Schachter et al. (1994) had identified ApoE2 allele as E4 [ E3 [ E2 so that E4 carriers have higher
being more frequent in French nonagenarians and this lipoprotein fractions and associated increased risk of
finding has been confirmed in other studies where not cardiovascular disease, dementia and stroke, com-
only was ApoE2 allele frequency accentuated but pared to E2 carriers (Bennet et al. 2007). BELFAST
carriage of the ApoE4 allele was reduced in nonage- nonagenarians who carried the ApoE4 allele showed
narian and centenarians cohorts (Frisoni et al. 2001; higher serum cholesterol values compared to those
Kervinen et al. 1994; Cauley et al. 1993; Eggertsen who carried the ApoE2 allele in keeping with the
et al. 1993; Corder et al. 1996). In keeping with this finding of increased vascular-related risk and attrition
hypothesis, BELFAST nonagenarians, showed a fall in effect on the ApoE4 gene pool in 90 year old
ApoE4 allele frequency reduced from 16 % in survivors. Changes in modern-day lifestyle have been
\65 year olds from the same geographical area, argued to be important in the present-day and
enlisted for the MONItoring of CArdiovascular atherosclerotic-related risk for ApoE function in
(MONICA) project, down to 8 % in BELFAST Western populations who have adopted higher fat
nonagenarians. There was a reciprocal change in diets and a less physical life-style. Raichlen and
ApoE2 allele frequency rising to 12 % in nonage- Alexander 2014 have argued and provide evidence
narians compared to 8 % in \65 year old MONICA that ApoE4, which is the ancestral variant, is negative-
local subjects (Rea et al. 2001). One of the main ly affected by smoking, high fat diet and a sedentary
explanations for these findings has been the association life-style but can be modulated by appropriate excise
of ApoE4 carriage with a more risky lipoprotein profile and diet regimes similar to those which were part of
(Bennet et al. 2007) which likely contributed to earlier the life-style of our ancestors. Emphasising the same
mortality through vascular disease affecting the brain theme, Mattson (2012) argues that the fast food and
and cardiovascular system. Hence the frequency of the the doorstep pizza delivery was not part of the life-
ApoE4 allele showed attrition in the oldest healthiest style of our ancestors who had to spend much more
nonagenarian and centenarian cohorts. physical energy in obtaining their daily energy needs
Added to this disease risk profile of the ApoE4 allele, (Mattson 2012).
the GeHA study of nonagenarian siblings (Beekman et al. One of the biggest conundrums is the association of
2013), clearly replicated the known stratification of ApoE the ApoE gene with both longevity and age-related
frequencies North–South in Europe with higher popula- disease (Perls 2002; Zhang et al. 2008). Does this
tion frequencies of ApoE4 in Northern Europe compared suggest that the life style factors which BELFAST
to Southern countries. This finding also appeared to track nonagenarians or the Perl ‘escaper’ phenotype (Evert
with the increased susceptibility of cardiovascular disease et al. 2003) have adopted are instrumental in delaying
risk. It is also known that ApoE4 frequency is much lower age-related diseases and vascular risk (Hagberg et al.
in some areas of the world (Corbo and Scacchi 1999) with 2000; Masson et al. 2003; Ordovas 2008) and that
a baseline frequency reported of 10 % at age 20 falling to through a combination of behavioural genetics and
4 % in the[1990s in Han Chinese, suggesting a similar life-style factors, ‘elite’ nonagenarians intuitively
attrition with age for ApoE4 allele but from a lower chose the different life experiences, diets and lifestyles
baseline population frequency (Jian-Gang et al. 1998; Lu best suited to them (Gibney and Walsh 2013)?
et al. 2014). Again there is the consideration that this
lower ApoE population frequency may associate with a TCF7L2 gene and Mediterranean diet
lower baseline frequency and risk of cardiovascular
disease early mortality. The relationship between the TCF7L2 and the
Mediterranean diet is one of the most recognised
gene/diet interactions (Corella et al. 2013). Strict
Diet, genes and life-style compliance with the Mediterranean diet can modulate
the damaging effects of the T risk allele which is an
ApoE and life-style factors important risk factor for development of diabetes.
Importantly, in the context of longevity, Garagnani
The allelic variants of ApoE are associated with et al. (2013) argued that centenarians could be used as
increasing cholesterol and lipid profile in the range ‘super controls’ to assess the biological significance of

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genetic markers for age-related diseases, for Type 2 (C) of the-174 G/C IL-6 polymorphism have higher
diabetes and the TCF7L2 genotypes. The group levels of IL-6 than do G genotype carriers and a
reported a marked reduced frequency of the dia- demonstrably increased risk from cardiovascular dis-
betes-related risk T allele of TCF7L2 in their super ease (Spoto et al. 2014). It was therefore argued that
centenarian controls, but an enrichment of the ho- the G-allele-carriers might be more common in those
mozygous CC genotype, suggesting that the CC who became nonagenarians or centenarians. In the
genotype could be a strong protective variant, at least local BELFAST nonagenarian cohort, the frequency
in Italian centenarians likely to have been exposed to a of homozygous IL-6 G allele showed some attrition in
Mediterranean diet. very aged persons but was insufficiently powered (Rea
et al. 2003). A subsequent European meta-analysis
demonstrated a shift in IL-6-G-allele frequencies
Good health and immunity North/South but showed no significant association
with longevity in the combined aged-cohorts (Di Bona
Cytokine genes et al. 2009). However a separate analysis of southern
European centres showed an increased odds ratio for
Cytokine genes control cytokines, which in turn drive the G-allele and longevity (Di Bona et al. 2009). Here
the immune response (McNerlan et al. 2009). Togeth- it was postulated that the IL-6 gene polymorphisms
er they orchestrate and maintain the immune system could be modulated by the Mediterranean diet as has
thorough out life and seem likely to have an important been noted in cellular studies (Mena et al. 2009;
role in good quality ageing and longevity. Cytokine Camargo et al. 2010) with the Mediterranean diet
polymorphisms have functional effects which deter- contributing to differences between Northern and
mine serum cytokine responsiveness to danger signals, Southern European incidence, and mortality from
including infections, cancerous cells, toxins, diet and vascular disease (Fung et al. 2009; de Lorgeril and
exercise (Ross et al. 2003; Rea et al. 2006). Consid- Salen 2006).
ering the continual pressures from internal and exter-
nal stressors, the immune system’s adaptability is Autoimmune disease and Mediterranean diet
being constantly shaped and re-shaped thorough out
life. It seems likely that there are different cytokine Similarly there is increasing evidence that autoim-
gene polymorphisms and phenotypes, some of which mune diseases such as rheumatoid arthritis or lupus or
contribute to the age-related disease phenotype and are ulcerative colitis may be modulated by compliance
perhaps associated with a strongly pro-inflammatory with a Mediterranean type diet (Skoldstam et al. 2003;
response, which could contribute to survival from McKellar et al. 2007) which appears to reduce the
childhood infections, but might drive immune activa- inflammatory profile of disease through mechanisms
tion with a predilection to age-related disease later in which are considered to be mediated through down-
life (Rea et al. 2006), while conversely another regulation of the NFkB pathway, which stands at the
cytokine phenotype could be associated with an cross-roads of the cellular inflammatory cascade
accentuated anti-inflammatory profile, a more (Lawrence 2009).
modulated immune response to mid life ‘stressors’
and/or age-related disease and contribute to a cytokine Diet, exercise and anti-oxidant status
profile, better shaped to facilitate longevity (Lio et al.
2002). In exercise-related stress there is evidence that anti-
oxidant capacity is important in reducing post-exer-
IL-6 and Mediterranean diet cise stress (Radak et al. 2008) and that a careful control
of anti-oxidant flux through diet may help to reduce
The IL-6 gene is called the gerontologist cytokine damaging post-exercise cytokine responses (Lamina
(Ershler 1993) and was considered a likely candidate et al. 2013). While a moderate amount of exercise is
in longevity and good quality ageing, because most considered good (Cobley et al. 2014; Radak et al.
age-related diseases are associated with increases in 2005) endurance and ultra marathon type sports
serum IL-6. Subjects homozygous for the risk allele can contribute to long-term damage and immune

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activation which does not settle between episodes and infections in the body (Al-Jaderi and Maghazachi
the positive and beneficial effects of ‘hormesis’ are 2013). In preliminary work, there is a small negative
lost (Lushchak 2014). relationship between NK cell number and BMI in
BELFAST nonagenarians (Rea et al. 2013) which
Genetics and NK cells replicates findings between BMI and anthropometric
measurements identified previously in Italian aged
Natural Killer cell (NK) populations have been found cohorts (Mariani et al. 1999; Ravaglia et al. 2000).
to be increased with increasing age (Miyaji et al. 1997; This finding could be important in relation to the
Sansoni et al. 1993; McNerlan et al. 1998). NK cells, obesity paradox which has described improved out-
together with related NKT subsets, the killer cell comes from life-threatening serious infections and
immunoglobulin-like receptor (KIR) receptor-gene- major surgical procedures in elderly people with
complexes and associated cytokine profiles, are highly higher BMIs (Hogue et al. 2009; Kuperman et al.
important in effective in patrolling, controlling and 2013).
protecting our immune landscape thorough out life
from viruses, cancerous and damaged cells of all kinds
(Peralbo et al. 2007; Rea et al. 2013. Their roles and Physical activity
interactions are likely to be important in maintaining
immune integrity in people who live successfully into Many of the nonagenarian cohort reported continuing
their 1990s and beyond (Mocchegiani and Malavolta to be physically active thorough out their lives. The
2004) and fit the criteria of the Perl ‘escaper’ model of nonagenarians are no longer alone in their belief that
successful ageing (Evert et al. 2003). The KIR genes one of the secrets of survivorship is working hard and
control the functions of NK cells through A or B maintaining physical activities. The Cambridge
haplotypes, with A having a more inhibitory role on University study of 334,000 people found that even a
NK function, compared to the more activating role of modest amount of physical activity prolonged life
B the KIR haplogroup. BELFAST nonagenarians (Ekelund et al. 2015), with similar findings in another
grouped by A and B KIR haplotype showed a large pooled cohort analysis (Moore et al. 2012). A
predominantly B haplogroup inflammatory cytokines prospective observational study involving almost half
profile for B haplogroup carriers but increased num- a million Taiwanese reported that being active for as
bers of NK cells for nonagenarians carrying the KIR A little as 15 min a day can add as much as 3 years to the
haplogroup (Rea et al. 2013; Maxwell et al. 2004). length of life (Wen et al. 2011) and a major study in
These differences in KIR haplotype effects may be USA has further shown that maintaining active
important in explaining the longevity phenotype with exercise was an important contributor to good quality
the increased number of NK and NKT-related cells ageing for male physicians, who reached 90 years of
found in nonagenarians (McNerlan et al. 1998; age in good health (Yates et al. 2008). In a recent
Peralbo et al. 2007) or conversely with the pro- systematic review of physical activity and healthy
inflammatory background found with increasing age ageing including cognitive function, there were clear
or inflamm-ageing (Franceschi et al. 2000). outcome findings suggesting that late-life physical
activity is beneficial for cognitive function in elderly
NK cells and diet people, with three studies reporting a dose–response
relationship between physical activity and cognition
NK cells do appear to have a relationship with (Carvalho et al. 2014). Although mechanisms remain
nutrition and diet. Their cytolytic activity of NK to be fully identified, brain-derived neurotrophic
receptors have shown to be upregulated by nutrition factor (BDNF) is known to be heavily involved in
measures including Vitamin D and anthropometric the differentiation, extension, and survival of neurons
markers (von Essen et al. 2010; Cantorna et al. 2012). in the hippocampus, cortex and cerebellum during
Scientists have found that vitamin D is crucial to brain development (Neeper et al. 1995; Vaynmana
activating our immune defences and that without et al. 2006), and some animal models (Rhyu et al.
sufficient intake of the vitamin D the killer cells of the 2010; Patten et al. 2013; Merkley et al. 2014) followed
immune system are not able to react to fight off serious by clinical studies, demonstrate that BDNF level is

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associated with hippocampal volume and with aerobic such as bereavement, deteriorating health and loss of
exercise (Pang and Hannan 2013; Lojovich 2010; autonomy (Northern Arizona University 1998) and to
Muscari et al. 2010; Erickson et al. 2011). mitigate negative feelings and emotions (Rentoul
These studies all add to the accumulating evidence 1997).
that says that exercise is good for everyone (Plough-
man 2008), irrespective of age and may also keep our
brains in sharper function by stimulating and main- Summary comments
taining neurogenesis.
The themes emerging from collected life stories
collected of ‘elite’ nonagenarians provide some
Genetic and molecular mechanisms of resilience insights into why nonagenarians believe they have
lived so long and well. Their narratives and answers
Social networks and resilience are an adjunct to a whole range of ongoing scientific
genetic enquiry using innovative new technologies
Successful ageing is considered to be more than the and bioinformatics to search out the genetics and life-
‘‘absence of disease and maintenance of high func- style patterns of longevity. Personal insights from
tioning’’ (Baltes and Baltes 1990), but involves the nonagenarians themselves provide important informa-
active engagement in everyday social activities. tion about beliefs, behaviours and social circum-
The value of good social networks and family stances which further enrich our understanding of the
interactions has been previously described as impor- ageing-well phenotype (Baltes and Baltes 1990).
tant in good quality ageing (Evert et al. 2003), with the We need to ask ourselves if the psychological
number of social interactions daily and inclusion in characteristics which nonagenarians demonstrate are
family networks making for good mental health and primarily genetic or cultural—or if the two are
social well-being (Rowe and Kahn 1997). inextricably linked through behavioural genetics? Do
Although much remains to be clarified, the our behaviours, our choices, our family and social
mechanisms through which stress can affect mental context influence and imprint our genes, so that each
and physical health and resilience are becoming new generation takes forward behaviours and family
clearer. Excessive glucocorticoids (GCs) released cultural influences in a way which to date cannot be
after early life stress exposure seem to cause long- measured, but only surmised from our understanding
lasting destabilisation of the stress hormone system of social networks, experiences and trans-generational
which in turn increases risk for later psychiatric influences (Laland et al. 2010; Heijmans et al. 2008;
disorders. These findings follow on the early work in Pembrey et al. 2014).
animal studies whereby poor maternal care was shown The insights related by nonagenarians about how
to cause dysregulation of the HPA axis in rodents with they understand their own good quality ageing,
altered transcription of the GC receptor gene (Meaney resonate with present-day public health campaigns
2001). Absence of early nurturing, through licking encouraging people to adopt better life-styles and
behaviour in rodent models, led to changes in the behaviours in order to set a better life course (Thaler
promoter of the GC receptor NR3C1 gene (Meaney and Sunstein 2008; Marteau et al. 2011; Department of
and Szyf 2005), with similar changes demonstrated in Health 2010). They are living examples of how a
people with bipolar disorders and later life stress combination of factors—family genes, behaviours and
which correlated with frequent general practice atten- beliefs and perhaps a healthy dose of good luck—seem
dance (Furukawa et al. 1999; Glaser et al. 2006; to have improved their chance of living longer and
Francis et al. 1999). with a better quality of life.
Around this theme, nonagenarians reported ‘being The message for everyone is that taking better care
happy’, ‘always cheerful’, ‘never melancholy’ and of ourselves, our social networks and actively making
having a contentment with a ‘rich life’ and family life-style choices can increase the chance of ‘ageing
relationships ‘thank God I have such good children’. long and ageing well’ and improve the longevity
Social networks and supportive relationships are dividend for each person and for society (Olansky
known to buffer the effects of stressful life events et al. 2007).

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Acknowledgments We thank the nonagenarians from the Chuang YF, Hayden KM, Norton MC, Tschanz J, Breitner JC,
BELFAST study who enthusiastically engaged in the Super Welsh-Bohmer KA, Zandi PP (2010) Association between
Vivere and Beyond 90 Together projects and shared their life APOE epsilon4 allele and vascular dementia: the cache
stories and their views on their healthy ageing with us. The county study. Dement Geriatr Cogn Disord 29:248–253.
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grant. (2014) Exercise improves mitochondrial and redox-
regulated stress responses in the elderly: better late than
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