**8. References**

232 Basic and Clinical Endocrinology Up-to-Date

In a cohort of Ashkenazi Jewish centenarians, a gender-specific increase in serum IGF-1 associated with smaller stature in female offspring was found to be due to heterozygous mutations in the IGF-1R gene (Suh et al. 2008). These rare mutations were significantly more common in female centenarians and overrepresented compared to controls (Suh et al. 2008). These observations are in line with the IGF-1R+/- mouse model, in which female mice show growth retardation and extended lifespan (Holzenberger et al. 2003) but IGF-1

Further studies on human centenarians, mainly screening selectively genes of the IIS pathway, identified certain genes in the insulin/IGF-1 pathway to be important for human longevity. Several cohorts with different genetic background have reported an association of FOXO3A single nucleotide polymorphisms (SNPs) with longevity (Willcox et al. 2008; Flachsbart et al. 2009; Anselmi et al. 2009; Pawlikowska et al. 2009; Li et al. 2009). Interestingly, the study on long-lived Han Chinese revealed a SNP of FOXO1 associated

Furthermore, in the Leiden 85-plus Study an association of a certain FOXO1 haplotype with higher HbA1c levels, higher prevalence of diabetes, myocardial infarction as well as increased mortality was observed (Kuningas et al. 2007). In addition, a certain haplotype of the FOXO3A gene revealed increased risks for stroke and mortality (Kuningas et al. 2007). These findings indicate that alterations within the FOXO genes might be causative involved

Recent studies in different model organisms, including *C. elegans*, *Drosophila melanogaster* and *Mus musculus* have generated piling knowledge about the IIS pathway and its relevance for healthy ageing and longevity. The data obtained in these model organisms have been translated to humans and lead to the identification of the IIS pathway as regulator for

The GH and IGF-1 signalling pathway plays a key-role in regulating growth and metabolism, and alterations within this pathway have crucial effects on health and lifespan. Model-organisms with reduced GH or IGF-1 signalling are frequently long-lived or show an increased mean lifespan. Interestingly, serum GH and IGF-1 levels decrease with age, and this might be interpreted not solely as progressive failure of the hypothalamus-somatotrope

IGF-1R signalling is required for normal brain development, and acute IGF-1 action might enhance cognitive functions and ameliorates ischemic or traumatic brain injuries. Additionally, recent studies demonstrate that IGF-1R signalling or the number of IGF-1Rs in the brain during early development determines metabolism and possibly age-associated diseases indicating a role of IGF-1 mediated signals as neuroendocrine regulator of health

Foxo-transcription factors have been identified as main downstream-target of IIS and seem to be essential for activating gene transcripton that mediates longevity. Furthermore, genomic screening of centenarians with different genetic background found matching SNPs or haplotypes in the FOXO3A gene suggesting a key-role of FOXO3A in influencing lifespan

However, the role of IIS in AD still raises questions, as the impaired signalling might be

in age-associated diseases and regulation of lifespan (Flachsbart et al. 2009).

axis but rather as protection for insulin resistance and malignancies.

not only in model organisms but also in humans.

cause or consequence of neurodegeneration.

resistance.

**7. Conclusion** 

and lifespan.

human lifespan and ageing.

with female longevity exclusively (Li et al. 2009).


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growth and development in the absence of hepatic insulin-like growth factor I. *Proc* 


**Part 6** 

**Endocrinology of Stress** 

Zigman, J. M., Y. Nakano, R. Coppari, N. Balthasar, J. N. Marcus, C. E. Lee, J. E. Jones, A. E. Deysher, A. R. Waxman, R. D. White, T. D. Williams, J. L. Lachey, R. J. Seeley, B. B. Lowell, and J. K. Elmquist. (2005). Mice lacking ghrelin receptors resist the development of diet-induced obesity. *J Clin Invest* 115 (12):3564-72.

**Part 6** 

**Endocrinology of Stress** 

260 Basic and Clinical Endocrinology Up-to-Date

Zigman, J. M., Y. Nakano, R. Coppari, N. Balthasar, J. N. Marcus, C. E. Lee, J. E. Jones, A. E.

development of diet-induced obesity. *J Clin Invest* 115 (12):3564-72.

Deysher, A. R. Waxman, R. D. White, T. D. Williams, J. L. Lachey, R. J. Seeley, B. B. Lowell, and J. K. Elmquist. (2005). Mice lacking ghrelin receptors resist the

**11** 

 *Spain* 

**The Endocrine Response to Stress -** 

The word stress is used extensively to name a situation of tension that can be applied to living organisms such as animals or plants but also to ecosystems or in geological phenomena. Nevertheless, the concept of biological stress is closely connected to the historic development of the meaning of this word by Hans Selye after his short paper in Nature (Selye, 1936), following a first approach by Walter Cannon who restricted the physiological changes of stress and injuries to the effects of catecholamines and the adrenal medulla. Other key contributions of Selye to the stress associated concepts were the word stressor, meaning the agent causing stress effects and the non-specificity of the neuroendocrine response, even after positive or negative stressors (Szabo, 1998). Being such a general and widely used concept, the term stress has received many definitions, some of them trying to characterize the phenomenon, others focusing the elicited response and others even including the types of stressors, i.e. symbolic or real (physical, chemical, pathogenic). Nevertheless, in all of them some key elements are included: A source or stressor, the non-

As a relevant physiological mechanism, the stress response by itself is not inherently bad. For example, glucocorticoids are released in animals in response to situations that are not normally regarded as stressful, including courtship, copulation and hunting. In addition, hormones which increase during stress periods, are also part of the reproductive process and induce hormonal cascades causing parturition in some species (Möestl and Palme, 2002). As an example, brine shrimp *Artemia* exposed under gnotobiotic conditions to a nonlethal heat shock increases the expression of Heat Shock Protein-70 (HSP-70), thus inducing a non-specific molecular stress response. When Artemia was challenged with pathogenic bacteria, *Vibrio campbellii* and *Vibrio proteolyticus*, a cross-protection against pathogens was observed if an appropriate combination of heat application and recovery treatment was

The overall stress response, meaning the array of reactions generated in most body compartments as a result of the threat of the stressor, is common to all organisms. The fightor-fight response and the fear reactions can be seen as a common behavior from

**1. Introduction** 

**1.1 The stress concept** 

applied (Sung et al., 2007).

specific reaction and the neuroendocrine response.

**1.2 Stress, a general phenomenon in living organisms** 

**A Comparative View** 

*Dpt. of Cell Biology, Physiology and Immunology* 

Lluis Tort and Mariana Teles

 *Universitat Autonoma de Barcelona* 
