Several microarray studies have now been performed in mice, rats, nonhuman primates, and humans to analyze the genetic profile of the aging brain. They all indicate that normal aging is not accompanied by a genome-wide dysregulation of transcription but rather by specific changes that affect only a small subset of genes, which accounts for about 3% to 5% of all the genes expressed in the brain. These changes (Table 62-2) will not be discussed here as their overall biological significance is still uncertain. Of note, a similar expression profile was also found in patients with Alzheimer disease supporting the view that a continuum might exist between normal aging and Alzheimer disease.
TABLE 62-2GENETIC PATHWAYS OF THE BRAIN THAT ARE AFFECTED BY AGING ||Download (.pdf) TABLE 62-2 GENETIC PATHWAYS OF THE BRAIN THAT ARE AFFECTED BY AGING
|Glucose metabolism ||Some up, some down |
|Fatty acid metabolism and transport ||Overall down |
|Mitochondria β-oxidation ||Overall down |
|Protein synthesis and modification ||Some up, some down |
|Protein turnover ||Overall down |
|Vesicular/protein transport ||Overall down |
|Stress response (antioxidant, DNA repair, metal ion homeostasis, etc) ||Overall up |
|Inflammatory molecules ||Overall up |
|Microglia activation ||Overall up |
|Neurogenesis ||Overall down |
|Growth factors ||Overall down |
|Myelination ||Overall up |
|Synaptic turnover and activity ||Overall down |
|Synaptic plasticity ||Overall down |
|Ca++ homeostasis ||Overall down |
|Intraneuronal signaling (kinases, G proteins, etc) ||Overall down |
|Hormonal regulation ||Some up, some down |
It is now evident that specific genetic, biochemical, and molecular pathways are intrinsically related to aging. Some of these pathways were initially identified in lower organisms and then later confirmed in higher organisms while others were immediately identified in higher organisms. These include the insulin-like growth factor 1 receptor (IGF-1R), Delta40p53, and Klotho.
Among them, IGF-1R has probably received more attention. The first evidence that IGF-1R signaling can regulate the progression of aging came from Caenorhabditis elegans where mutations that reduce IGF-1R activity were able to increase the lifespan of the animal. Similar results were then obtained in Drosophila melanogaster and, later on, in mammals. Importantly, mutations that act on IGF-1R downstream targets were also able to modify the lifespan of the animals providing robust and definitive connection between IGF-1R and aging. Overall, reduced IGF-1R activity extends lifespan and delays age-associated events while increased IGF-1R activity achieves the opposite effects. A partial block of IGF-1R signaling is also achieved by caloric restriction, which extends the maximum lifespan and delays many biological changes that are associated with aging. In humans, genetic variations that cause reduced IGF-1R signaling appear to be beneficial for old age survival and preservation of cognitive functions, suggesting that the mechanisms regulating lifespan and aging via this pathway are evolutionary conserved. Finally, reduced IGF-1R signaling can rescue Alzheimer disease in mouse models.
Delta40p53 is a short N-terminal truncated isoform of the tumor suppressor gene TP53. The common TP53 gene generates at least 12 different proteins through a combination of alternative promoter usage, alternative splicing, and alternative initiation of translation. Of them, p53 is the most “famous” and most studied due to its pathogenic role in many forms of cancer. Delta40p53 (also referred to as p44 or p47) lacks the first N-terminal 39 amino acids of full-length p53 but retains the DNA-binding domain as well as one of the two transactivation domains. Delta40p53 retains some of p53 functions but lacks others; it retains some of the regulatory elements but lacks others. Mice overexpressing full-length p53 (“Super p53” mice) are resistant to cancer development but have normal maximum lifespan. In contrast, mice overexpressing Delta40p53 (p44+/+ mice) display a progeroid phenotype that mimics an accelerated form of aging. The phenotype includes early onset of diabetes, osteoporosis, memory impairment, and reduced lifespan. To date at least five additional mouse models with altered p53 activity have been shown to develop an accelerated aging phenotype providing robust and definitive connection between TP53 and aging. Recent studies have also shown that Delta40p53 regulates the generation of Aβ as well as the phosphorylation status of tau, suggesting a possible connection with the accumulation of amyloid plaques and neurofibrillary tangles that characterizes the aging as well the Alzheimer disease brain (discussed earlier in this chapter). Interestingly, mice engineered to overexpress p44 develop an accelerated form of Alzheimer disease neuropathology.
Klotho is a cell-surface membrane protein that can also be released in the circulation. Klotho has glycosidase-like activity. Its levels and enzymatic activity decline during aging. Genetic variants of KLOTHO are associated with human aging and klotho-deficient mice display a progeroid phenotype that resembles aging. The phenotype includes atherosclerosis, skin atrophy, osteoporosis, reduced fertility, emphysema, memory defects, and reduced lifespan. In contrast, mice overexpressing klotho display increased lifespan and increased resistance to several age-associated features. A possible connection between klotho and IGF-1R has also been delineated. Human variations that lead to increased circulating levels of klotho are associated with greater cortical volumes in the brain. Finally, overexpression of klotho in the mouse enhances cognition and rescues some of deficits that characterize Alzheimer disease.
In addition to the above, polymorphisms that are associated with longevity and preserved physiologic functions have also been identified in two cholesterol-related genes, apolipoprotein E (APOE) and cholesteryl ester transfer protein (CETP). APOE carries cholesterol in the circulation while CETP facilitates the transfer of cholesteryl esters and triglycerides between circulating lipoproteins. Individuals normally inherit two APOE alleles, of which there are three isoforms (E2, E3, and E4). The E2 allele has been linked to longevity and reduced incidence of Alzheimer disease. In contrast, the E4 allele has been linked to increased risk for Alzheimer disease. Certain CETP variants have been linked to increased levels of high-density lipoproteins (HDL), reduced progression of atherosclerosis, and longevity. The “longevity effect” of APOE and CETP might be explained, at least in part, by their ability to reduce the progression of atherosclerosis in the vasculature.
Another possible longevity gene is that encoding an isoform of angiotensin-converting enzyme, although its mechanistic links to aging are unclear. Finally, the multigene major histocompatibility system appears to influence lifespan, and may act by sustaining functions of the immune system. Additional information on longevity genes and their impact in age-associated events can be found in Chapter 1.
Considerable progress has been made in characterizing human genetic disorders that cause progeroid syndromes, which are characterized by a disease phenotype mimicking an “accelerated” form of aging. Although progeroid syndromes can be classified as unimodal (affecting one tissue/organ) and segmental (affecting multiple tissues/organs), the term progeroid syndrome is usually limited to the segmental forms of the disease (Table 62-3). Examples include Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford progeria syndrome, and Cokayne syndrome. Patients affected by these disorders have limited lifespan and develop a complex array of disease manifestations, including type 2 diabetes, osteoporosis, hair loss, skin atrophy, atherosclerosis, cardiomyopathy, heart failure, chronic obstructive pulmonary disease, renal insufficiency, and neurologic abnormalities. The neurologic defects are often subtle and difficult to diagnose; when evident, they include bulbar, extrapyramidal and cerebellar symptoms, deafness, retinopathy, cognitive deficits, corticospinal symptoms, and peripheral neuropathy. Brain imaging shows diffused white matter pathology as well as different degrees of gray matter pathology in memory-forming and -processing areas. The genetic defect has been mapped in most classical forms of progeroid syndromes. Specifically, Werner syndrome has been associated with mutations in WRN; Bloom syndrome has been associated with mutations in BLM; Rothmund-Thomson syndrome has been associated with mutations in RECQL4; Hutchinson-Gilford progeria syndrome has been associated with mutations on LMNA; and Cokayne syndrome has been associated with mutations in ERCC8 and ERCC6. All the above genes encode proteins that are involved in different aspects of DNA transcription, repair, or recombination underscoring common pathogenic elements.
TABLE 62-3SEGMENTAL PROGEROID SYNDROMES WITH COGNITIVE CHANGES ||Download (.pdf) TABLE 62-3 SEGMENTAL PROGEROID SYNDROMES WITH COGNITIVE CHANGES
|SYNDROME ||INHERITANCE ||MEAN LIFESPAN (Y) |
|Ataxia-telangiectasia ||Autosomal recessive ||~ 45–50 |
|Berardinelli-Seip syndrome ||Autosomal recessive ||~ 40 |
|Bloom syndrome ||Autosomal recessive ||Unclear |
|Cokayne syndrome ||Autosomal recessive ||~ 20 |
|Down syndrome ||Trisomy 21 ||~ 60 |
|Hutchinson-Gilford progeria ||Autosomal dominant ||~ 10–15 |
|Rothmund-Thompson syndrome ||Autosomal recessive ||Unclear |
|Trichothiodystrophy ||Autosomal recessive ||~ 10 |
|Werner syndrome ||Autosomal recessive ||~ 45–50 |
Although progeroid syndromes manifest with symptoms and physical features that are—at least in part—reminiscent of an accelerated form of aging, they must be viewed as diseases rather than true forms of accelerated aging. It is plausible to assume that the dissection of the molecular phenotype of these diseases will inform us about aging. However, it is also plausible to expect that the underlying defects of human progerias are substantially different from those of normal aging. Additional discussion of human progerias can be found in Chapter 1.
Considerable progress has also been made in identifying genetic factors that play pathogenic roles in Alzheimer disease, the most common form of dementia associated with aging. Specifically, disease-causing mutations in APP, PSEN1, and PSEN2 have been identified in familial (early-onset) forms of Alzheimer disease. In addition, several “predisposition” genes have been identified in which polymorphisms increase the risk for developing sporadic (late-onset) Alzheimer disease. Description of the most important polymorphisms identified to date as well as pathogenic roles of APP, PSEN1, and PSEN2 can be found in Chapter 66.
The Brain as a Regulator of Lifespan
Among the very first mouse models of extended lifespan were the Ames and the Snell dwarf mice. Both models had a selective defect in the secretion of key hormones from the pituitary gland, specifically, growth hormone (GH), prolactin, and thyroid-stimulating hormone. The 40% to 60% extension of lifespan was also accompanied by evidence of delayed aging. The increased lifespan of the Ames and Snell mice was primarily linked to the deficiency of the GH-IGF1 axis. GH is released in the circulation by the pituitary gland; upon binding to its own receptor in the liver, it causes secretion of IGF1, which then binds to IGF-1R and stimulates IGF-1R signaling. Mice with isolated deficiency in growth hormone secretion (Little mice) or lacking the growth hormone receptor (GHR-KO mice) also displayed longevity. The lifespan extension in the Little and GHR-KO mice was in the 25% to 55% range. Finally, mice with reduced secretion of IGF1 or reduced levels of IGF-1R also displayed different levels of increased lifespan. In essence, the Ames and Snell mice represent the very first evidence that the brain itself (or specialized sets of neurons in the brain) could influence the lifespan of the animals. Following studies in lower organisms (C elegans and D melanogaster) clearly confirmed this conclusion. More recently, genetic disruption of IRS2, an adaptor protein that acts downstream of IGF-1R and the insulin receptor, in the mouse brain (bIrs–/+ and bIrs–/–) also caused a significant increase in the lifespan of the animals. Regardless of the specific mechanism(s) involved in the phenotype of the above genetic models, it is now well accepted that in addition to being affected by aging, the brain (or the nervous system) itself can affect aging.