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Langlebigkeit und Altern: Gene oder Umwelt?

Zusammenfassung

Altern wird definiert als Verlust der Homöostasefähigkeit, welche alle Stoffwechselvorgänge einschließlich unserer DNA einschließt. Interspezies Vergleiche und die Erkenntnisse der genetischen Instabilitätssyndrome beim Menschen zeigen eine eindeutige Korrelation zwischen DNA-Homöostase und der maximalen Lebensspanne, während die durchschnittliche Lebensspanne einer Population überwiegend von Umweltfaktoren abhängt. Die Ergebnisse von demographischen Untersuchungen suggerieren eine derzeitige Begrenzung der maximalen Lebensspanne bei 110–115 Jahren. Die durchschnittliche Lebenserwartung hat sich im Verlaufe des 20. Jahrhunderts in den Industrienationen von ca. 40 auf ca. 80 Jahre verdoppelt. Extrapolationen sprechen für einen weiteren Anstieg der durchschnittlichen Lebenserwartung (zumindest von Frauen) auf über 90 Jahre. Überwiegend genetische und biologische, jedoch auch „lifestyle“ Faktoren sind für die durchschnittlich höhere Lebensspanne von Frauen verantwortlich. Es ist bisher nicht gelungen, einen „Langlebigkeits“-Genotyp zu definieren, jedoch besteht ein eindeutiger Nachteil für Träger des ApoE4-Allels. Im Gegensatz zur Situation bei vielen Modell-Organismen werden Altern und Langlebigkeit beim Menschen offenbar durch das Zusammenspiel von zahlreichen Genen und Umweltfaktoren bestimmt. Die meisten Menschen sterben auch nicht an Altersschwäche, sondern an alterskorrelierten Krankheiten, die z.T. durch Gendefekte bedingt oder mitbedingt sind. Die Häufigkeit von Alterkrankheiten erklärt sich u. a. durch die fehlende Selektion gegen Genveränderungen, welche sich erst nach Abschluss der Reproduktion als Krankheit manifestieren. In der Jugend können diese Gendefekte sogar positive Auswirkungen haben und dadurch zur physischen und reproduktiven Fitness beitragen (Prinzip der antagonistschen Pleiotropie). Als essenzielle Gene können sie nicht aus unserem Genom entfernt werden. Genauso wenig können wir die natürliche Thermoinstabilität unserer DNA bei 37 Grad Körpertemperatur oder die Generierung von freien Sauerstoffradikalen als Nebenprodukt der Energiegewinnung durch oxidative Phosphorylierung eliminieren. Diese endogenen Prozesse bedingen die mit dem Alter zunehmende genetische Instabilität unserer Somazellen und begrenzen letztlich unsere Lebensspanne. Sie können ohne eine grundlegende Veränderung unserer biologisch-genetischen Grundstruktur nicht korrigiert werden. Die menschlichen Caretaker-Gensyndrome haben gezeigt, dass genetische Instabilität zur Krebsentstehung führt und den Alterungsprozess beschleunigt. Aus genetischer Sicht können Krebs und Altern durch optimale Lebensweise und/oder medizinische Intervention verzögert, jedoch nicht grundsätzlich besiegt werden.

Abstract

Aging is defined as loss of homeostasis which affects all metabolic systems, including DNA. Interspecies comparisons and lessons from the human genetic instability syndromes suggest a correlation between DNA-homeostasis and maximum lifespan, whereas average lifespan depends mainly on environmental factors. Current demographic data suggest a maximum lifespan in humans of 110–115. The average life expectancy at birth has reached 80 years in the wealthy nations and may exceed, at least in females, 90 years by the year 2050. Genetic and biological reasons, but also lifestyle factors, account for the greater longevity of women. Attempt to define a „longevity“ genotype so far have not been met with success, but carriers of the ApoE4-Allele appear to have a disadvantage. Unlike the situation in model organisms, aging and longevity in humans seem to be influenced by numerous genes and environmental interactions. Most people do not die of old age but of age-related diseases which are frequent because of lack of natural selection against genetic defects that cause late-onset diseases. Moreover, genes causing late-onset diseases show evidence of antagonistic pleiotropy, rendering these genes resistant to removal from our genome. Likewise, thermoinstability of DNA and generation of reactive oxygen species during oxidative phosphorylation are two endogenous sources of genomic instability that limit our lifespan and cannot be overcome without fundamentally altering the biological make-up of our species. Genomic instability causes cancer and accelerates the aging process, as evidenced by the human caretaker gene syndromes which typically show progeroid features. From a genetic point of view, cancer and aging may be moderately delayed and / or mitigated by lifestyle and medical / environmental interventions, but given the constraints of our biological make-up, they cannot be eradicated.

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Höhn, H. Langlebigkeit und Altern: Gene oder Umwelt?. Zeitschr. f. d. ges. Versicherungsw. 91, 237–258 (2002). https://doi.org/10.1007/BF03190765

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