Ageing and lifespan in GHIGFldeficient mice

Several mouse models with GH/IGF1 deficiency are available to study the influence of these hormones on ageing and longevity (lifespan). Due to the IGF1 deficiency all homozygous affected mice are dwarfed and they divide as the human models into MPHD including GH (e.g. the Ames dwarf mice and the Snell dwarf mice) and primary IGF1 deficiency (the Laron mouse).

The A mes dwarf mice (df/df)

These mice first described by Schaible & Gowen (1961) have a mutation in a transcription factor for all anterior pituitary hormones (GH, prolactin, thyroid-stimulating hormone and sex hormones) called Prophet of Pit.1 (Prop-1) (Sornson et al 1996), which is located on chromosome 11. Homozygous mice for the df/df mutation are dwarfed, and have a longer life span than control animals, which is not related to caloric intake or the reduced body temperature (Bartke

Snell dwarf mice (dwjdw)

Described in 1929 this type of dwarfed mouse has been subsequently shown to be caused by a mutation of the transcription factor Pit-1 (Li et al 1990) which is involved in the differentiation of somatotrophs, lactotrophs and thyrotrophs (Sornson et al 1996). Phenotypically, the Ames and Snell dwarfed mice are very similar with the exception that in Snell mice the gonadal development is more advanced.

Snell mice have extremely low serum levels of IGF1 (van Buul Offers et al 1986). They have also been described to have delayed ageing and a longer lifespan than normal animals from the same strain (Bartke 2000).

The ageing symptoms of these two types of MPHD mice are their retarded sexual development, reduced activity (not in all), progressive obesity and hair

% deceased/group

FIG. 5. Increased longevity in Ames dwarfed mice compared to normal controls of the same breed. Reproduced with permission from Bartke (2000).

% deceased/group

FIG. 5. Increased longevity in Ames dwarfed mice compared to normal controls of the same breed. Reproduced with permission from Bartke (2000).

loss (in part of the animals). Nevertheless, these animals appear to remain in excellent general condition for longer periods than their normal siblings (Bartke 2000). A group of Ames dwarfed mice outlived a control group of normal mice by more than one year (Bartke 2000) (Fig. 5). This extension of lifespan was longer in female mice.

The GH receptor/BP gene-disrupted mice (the Laron mouse)

A model of isolated IGF1 deficiency was created by disrupting the GH receptor (GHR) gene in mice (Zhou et al 1997). This model bears many similarities to the human primary GH resistance (GH insensitivity, i.e. Laron syndrome) (Kopchick & Laron 1999), such as high GH and low IGF1 and IGF binding protein (IGFBP)3 levels, dwarfism and organomicria, typical characteristics of Laron syndrome (Laron 1999b). Calculating average lifespans for each genotype (+/+, +/ —, — / —) and gender, we observed that the homozygous mice for the GHR mutation had a significantly longer lifespan than the unaffected and heterozygote mice (Coschigano et al 2000) (Table 3).

TABLE 3 Lifespan of GHR/BP gene-disrupted mice

Gender

Genotype

n

Lifespan (days) *

Males

+/+

7

629 + 72

+/-

8

668 + 51

-/-

7

975+ 106a

Females

+/+

13

749 + 41

+/-

19

701 + 36

-/-

11

aP 5 0.02 compared to +/+. bP< 0.005 compared to +/+.

Reproduced with permission from Coschigano et al (2000).

aP 5 0.02 compared to +/+. bP< 0.005 compared to +/+.

Reproduced with permission from Coschigano et al (2000).

GH transgenic mice

In contrast to the previously described observations, prolonged elevation of serum GH, as occurs in GH transgenic mice, is associated with a reduced lifespan (Bartke 1998), which may reach half of that in normal mice of the same species. This is similar to findings in patients with acromegaly. Thus, the question arises whether high levels of GH increase mortality. In effect, treatment of rats with high doses of GH accelerates the death of the animals (Groesbeck et al 1987). Although the conditions may be different, one should remember that GH treatment of chronically ill patients in intensive care units was also found to increase mortality (Takala et al 1999).

At present it is not clear how GH/IGF1 deficiency prolongs the lifespan in mice. It is possible that certain genes are involved. Mutations of a recently described insulin receptor like-gene, Daf2, result in increased longevity (Kimura et al 1997). This receptor, possibly homologous to the mammalian IGF1 receptor, mimics primary IGF1 deficiency. Nor do we fully understand how GH excess shortens the lifespan. This may be partly due to the water and electrolyte retention induced by GH/IGF1 and/or by the well-documented cardiotrophic effects of these hormones.

Although it may sound anecdotal it should be mentioned that there is evidence that within species, lifespan is negatively correlated with body size. Thus dogs from small breeds live longer than dogs from large breeds and small mice live longer than large mice (Bartke 2000). Last but not least, food-restricted animals (which are smaller), live longer than those fed ad libitum (Masoro 1992), with the exception of Ames and Snell mice.

Better Mind Better Life

Better Mind Better Life

Get All The Support And Guidance You Need To Be A Success At A Better Life. This Book Is One Of The Most Valuable Resources In The World When It Comes To Better Living with Enhanced Mental Health.

Get My Free Ebook


Post a comment