State of the art of the projects Madrid + 90 and Braga + 90

Although the definition of longevity is somewhat arbitrary, successful ageing could be defined in terms of two parameters: (1) that the biological age, whatever its determination, is less than the chronological age; and (2) that the ability to autonomously perform daily activities is relatively preserved.

The accumulated scientific evidence suggests that different mechanisms of genetic, environmental, cultural and/or geographical origin are involved in longevity. This means that there are heterogeneous factors in constant interaction among themselves capable of conditioning the rate of aging. The knowledge of these factors, as well as of their multiple interactions, will propitiate the implementation of interventions of different nature with the purpose of preventing the appearance of diseases associated with age and of improving the quality of life of the elderly.

Demographic change

Progress during the twentieth century in the social and environmental spheres, as well as in health care and quality of life, has led to an overall improvement in the health status of the population and, consequently, a reduction in mortality. As a result, life expectancy in Europe has increased markedly over the last century and is expected to continue to do so in the coming decades (Teixeira, Araújo, Jopp, & Ribeiro, 2017). According to EUROSTAT, Spain (18.7% of the population over 65; 28.2% in rural areas) and Portugal (20.7%) are among the oldest countries in Europe (Figure 1). In addition, the projections of this organism for the member countries of the European Union predict that the population over 80 will go from representing 1.2% in 1950 to 11.8% in 2050. These demographic projections are also in line with those predicted by the National Statistics Institute (INE), which expects a progressive growth in the segment of the Spanish population over 65, going from representing 16.9% of the total population in 2010 to 36.8% in 2050. Thus, in that year one out of every three people over 65 will be over 80 and that the percentage of people aged between 90-94, 95-99, and 100 or over, will increase by 284%, 441% and 922% respectively. The combination of this fact together with one of the lowest birth rates will make the Spanish population the oldest in Europe and one of the oldest in the world. These trends also appear in the Portuguese population, where the number of people over 80 has doubled in the last 20 years.

Figure 1: percentage of the largest population in Europe (taken from "Eurostat regional yearbook 2014").

This high level of population ageing is particularly marked in rural areas and in particular in the cross-border area between Spain and Portugal. According to EUROSTAT, Ourense, Zamora and Lugo in Spain and Pinhal Interior Sul in Portugal constitute four of the 10 oldest EU regions in Europe (Figure 2). For this reason, care policies for the elderly cannot be homogeneous in budgetary terms and, therefore, the regional singularity must be recognised in the policies for distributing budgetary funds for inter-territorial compensation.

Figure 2: population structure by age group (taken from "Eurostat regional yearbook 2014").

While this strong demographic change poses major challenges to society in economic, health and ethical terms, this unprecedented situation presents a crucial opportunity to understand the determinants of healthy ageing and longevity. Nineties and centenarians, commonly referred to in the scientific literature as "oldest old", can no longer be seen as a statistical anomaly, but as a growing segment of the population that can help identify key factors related to successful ageing.

Longevity Research Study Methodology

Long-lived subjects have usually been studied using two different and complementary approaches. Firstly, through the follow-up of cohorts of subjects, such as the Georgia Centenarian Study (Poon et al., 2007), the New England Centenarian Study (Perls, Bochen, Freeman, Alpert, & Silver, 1999) or the Sydney Centenarian Study (Sachdev et al., 2013), among others. All of these studies have very large catchment areas that allow them to recruit a large number of subjects, but at the cost of having a heterogeneous population that does not share genetic traits, socio-cultural characteristics or lifestyles. On the other hand, there are other types of studies that are limited to investigating long-lived subjects residing in small regions where the populations present specific characteristics; these regions, called "Blue Zones", are limited areas with a high prevalence of centenary people, with much more homogeneous characteristics, lifestyles and environmental variables. A sample of such Blue Zones can be found in Okinawa (Japan) (Willcox, Willcox, & Suzuki, 2017; Willcox, Willcox, Hsueh, & Suzuki, 2006), on the Nicoya Peninsula (Costa Rica) (Rosero-Bixby, Dow, & Rehkopf, 2013), on the island of Ikaria (Greece) (Stefanadis, 2011) or in Trieste (Italy) (Tettamanti & Marcon, 2018). Analysing their social habits, the environment in which they live or the diet they follow can provide key information to understand the ageing process.

Factors associated with longevity

Regardless of the methodology used to analyse the phenomenon of longevity, the study of very old individuals who have aged in a healthy way is very promising; this line of research could help to decipher the combination of lifestyle factors, therefore modifiable, that make it possible to prevent age-related illnesses, especially dementia. Variables such as diet, physical activity, economic status, education, social relationships, stress or socio-cultural context have been repeatedly researched and are pieces of a puzzle to increase life expectancy and quality.

Lifestyle factors can be classified into two groups according to their susceptibility to being easily modifiable or not. This classification will be decisive in establishing individual personalized longevity strategies (Rodríguez- Pardo del Castillo & López-Farré, 2017):

- Sociodemographic factors, not easily modifiable: income level; place of residence; possibility of access to socio-health resources; environmental pollution; marital status; employment.

- Specific lifestyle factors, potentially modifiable: diet; overweight; level of physical activity; level of intellectual activity; hours and quality of sleep; participation in family and social networks; strategies for coping with stress.

The accumulated evidence has allowed us to understand some of the variables associated with healthy aging. Among others, we can point out the following findings related to longevity:

- Taking care of weight and exercising periodically provides protection against mortality; especially, the lowest mortality risk is established when the Body Mass Index is between 20 and 25 kg/m2 (Berrington de Gonzalez et al., 2010).

- Short-term caloric restriction improves markers of delayed aging, such as serum glucose and insulin levels (Ingram et al., 2004). With respect to diet, especially the regular consumption of fruits, vegetables, nuts and legumes is associated with a greater likelihood of achieving extreme longevity.

- There is greater resilience or greater efficacy in managing daily stress (Hadley et al., 2017).

- Social activity and support groups are positively associated with longevity. In particular, it has been shown that lack of strong social relationships has a mortality risk equivalent to smoking (Holt-Lunstad, Smith, & Layton, 2010). Conversely, having a purpose in life is associated with a lower risk of mild cognitive impairment and dementia (Boyle, Buchman, Barnes, & Bennett, 2010).

- Delaying childbearing until after age 35, or even 40, increases the probability of living to 100 by up to four times (Perls, Alpert, & Fretts, 1997). This relationship is attributed to the fact that it is probably an indicator that a woman's reproductive system ages slowly, which can be extrapolated to the rest of her body.

- At least 50% of centenarians have first-degree relatives who have also reached a very advanced age, and many even have exceptionally older siblings. It has been shown that male siblings of centenarians are 17 times more likely to reach the age of 100 (Perls et al., 2002).

- The ε2 allele of the APOE gene has been associated with a higher probability of living longer (Pignolo, 2019).

Longevity and dementia

Distinguishing between normal aging and pathological aging in the elderly is particularly difficult. The lack of adapted and validated cognitive assessment tools for this population group, together with the lack of operational definitions of cognitive impairment, make diagnosis difficult in people over 90 years of age (Giulioli & Amieva, 2016).

Compared to younger older people, individuals over 90 have greater variability in the functional plane that increases the difficulty for their clinical, social and cognitive study. In addition, as a collateral effect to their exceptional longevity, there is a high percentage of people over 90 with sensory (visual or auditory) and/or psychomotor disabilities, which is an impediment to carry out any proposed neurocognitive examination (Gussekloo, de Craen, Oduber, van Boxtel, & Westendorp, 2005). In fact, there is an evident lack of consensus about the criteria for diagnosing dementia from the age of 90 (Slavin, Brodaty, & Sachdev, 2013).

While there is a degree of agreement between the prevalence figures for dementia in people aged 65 to 85, there are notable discrepancies between the existing data from the 1990s onwards. In this sense, some studies have suggested a decrease in the prevalence of dementia in very old people with respect to earlier ages (Fichter, Meller, Schröppel, & Steinkirchner, 1995), obtaining dementia rates in people over 90 years of 22.1% for men and 30.8% for women (Lobo et al., 2000), which stagnate around 40% at age 95 (Ritchie & Kildea, 1995), or even show a deceleration in prevalence-incidence/age (Gao, Hendrie, Hall, & Hui, 1998). But on the other hand, more recent studies indicate that both the incidence and prevalence of dementia continue to increase in this age group (Carrillo-Alcalá & Bermejo-Pareja, 2008; Corrada, Brookmeyer, Berlau, Paganini-Hill, & Kawas, 2008), and that it could even do so with the same rate of doubling as in the less elderly age groups (Corrada, Brookmeyer, Paganini-Hill, Berlau, & Kawas, 2010). Specifically, in centenarians, dementia prevalence rates are even more contradictory, with percentages ranging from 25-100% depending on the studies (Blansjaar, Thomassen, & Van Schaick, 2000). All these discrepancies could be explained, at least in part, due to the lack of systematic research in the oldest-old and the extreme complexity of precisely defining the diagnostic criteria.

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