The biology of aging

5. Human pathologies of aging
Some mutations found in rare human diseases seem to accelerate the appearance and the progression of tissue degeneration as in aging11.
In Werner Syndrome, patients suffer a multitude of phenotypes of aging, with various tissues being affected. Adult patients show a reduced height, hypogonadism, binocular cataracts, osteoporosis, arteriosclerosis, peripheral neuropathy, benign and malign neoplasies. Patients usually die of heart attack or cancer. Patients’ cells cultured in the laboratory display a senescent phenotype, with a complex pattern of genomic aberrations (mainly translocations and deletions). Recently, biologists have found that in Werner Syndrome the pathology is caused by mutations in a gene encoding for a protein involved in DNA repair, replication, recombination and transcription. This discovery highlighted the relevance of genomic instability in many pathologies of premature aging.
Ataxia Telangiectasia (ATM) is another human disease in which patients show premature aging. ATM is a genetic disorder that causes a progressive loss of Purkinje cells in the cerebellum and a vast array of neoplasies. Patients are hypersensitive to ionizing radiations. The genetic basis for ATM is a mutation in a gene encoding for a protein involved in DNA double strand break repair. ATM protein is usually active during cellular responses to oxidative stress.
In Juvenile Progeria, children have severe mental retardation, loss of subcutaneous fat deposits and abnormal cartilaginous tissue and they usually die at a young age of heart attack. Recent studies have identified in patients with Juvenile Progeria mutations in the genes for Lamin A and C. Such mutations cause an altered structure of the nuclear membrane, with consequences on cellular metabolism and a phenotype of premature aging.
Other diseases associated with premature aging show a clear link to genomic instability. Bloom Syndrome, Xeroderma Pigmentosa, Nijmegen Breakage Syndrome and Fanconi Anemia all display a defect in the ability to maintain genome integrity.

6. Anti-aging therapy

Pharmaceutical companies are currently developing a new class of drugs aimed to modify the aging process per se12. This novel approach requires the identification of the metabolic pathways of aging and of the potential molecular targets. Efforts have mainly focused on the following aspects:
1. metabolic pathway of Insulin/IGF-1 signaling,
2. reduction of reactive oxygen species in the mitochondria,
3. reduction of food intake,
4. increase of anti-oxidant molecules,
5. maintenance of telomere length.
The discovery of molecules and molecular mechanisms in invertebrates with a short life span points to new exciting options for higher vertebrates. Since the number of drug treatments that can be followed in clinical trials is unfortunately quite small, it is of vital importance to screen conserved metabolic pathways to connect multiple strategies apparently distant. Only when data obtained in animal models will be comprehensive, potential drugs will be tested in clinical trials. In the past, eight-years long clinical trials have succeeded in proving the principles: it is feasible to test drugs as modifiers of the aging process and of the side effects of aging (mainly the development of pathologies connected with increased longevity). On the contrary, if the aim is the validation of a candidate drug to slow the aging process, the clinical trial should start at much earlier stages, creating complex logistics. It becomes therefore mandatory to identify biological markers of aging for validating the pharmacological effects of a candidate drug in relatively short times.

11 Martin, G.M. (2005): “Genetic modulation of senescent phenotypes in Homo sapiens”, Cell, no. 25, 120 (4), pp. 523-32.
12 Medawar, P.B. (1952): An unsolved problem of biology, Lewis, London.

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