In Search of Methuselah: Estimating the Upper Limits to Human Longevity

Sj, Olshansky; Ba, Carnes; Cassel, Christine K.

doi:10.1126/science.2237414

Cited by 520 publications

(259 citation statements)

References 30 publications

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“…In contrast, the ability of caloric restriction to retard, in parallel, age-dependent changes in mitotic and nonmitotic cell types, extracellular macromolecules, and intercellular control pathways is difficult to reconcile with models based on multiple clocks, and thus supports models in which a very small number of fundamental timing processes acts to speed up or slow down age-dependent change in multiple domains. Because age at death is changed only slightly by changes in the risk of individual forms of disease (34), it seems unlikely that single gene mutations that extend longevity do so by an influence on a single form of disease; extensive data on terminal pathology, not yet available for any genetic model of longevity, are needed to address this question explicitly. Single gene mutations that extend lifespan thus provide prima facie evidence for the idea that multiple late-life processes-including multiple forms of illness-can be decelerated in parallel by some underlying control mechanism.…”

Section: Discussionmentioning

confidence: 99%

Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production

Flurkey

Papaconstantinou

Miller

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

770

586

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Single-gene mutations that extend lifespan provide valuable tools for the exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of agedependent diseases. We show here that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a >40% increase in mean and maximal longevity on the relatively long-lived (C3H͞HeJ ؋ DW͞J)F1 background. Mutant dw J ͞dw animals show delays in age-dependent collagen cross-linking and in six age-sensitive indices of immune system status. These findings thus demonstrate that a single gene can control maximum lifespan and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into dwarf mice does not reverse the lifespan effect, suggesting that the effect is not due to lowered prolactin levels. In contrast, homozygosity for the Ghrhr lit mutation, which like the Pit1 dw mutation lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se. Further studies of the Pit1 dw mutant, and the closely related, long-lived Prop-1 df (Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease.T he analysis of single-gene mutations in flies (1) and nematode worms (2-4) has begun to yield important clues to the molecular basis of aging and genetic control of longevity in invertebrates. At present there are four examples of single gene mutations that extend longevity in mammals (5-8). The best documented of these is the Ames dwarf mutation, now known as Prop-1 df , which in homozygous form has been shown to extend longevity by Ͼ50% in both males and females (5). Homozygous df͞df mice show defects in embryonic development of the anterior pituitary that lead to an absence of cells responsible for the production of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL). The small body size of these mice is apparent within the first 3 weeks of age, and young adults are approximately one-third of the size of ϩ͞df or ϩ͞ϩ littermates, which are themselves phenotypically indistinguishable from one another. Extended longevity (about 20%) and small body size also are seen in transgenic mice that express high brain levels of urokinase-type plasminogen activator (6); in this case the phenotypes are thought to reflect a loss of appetite and diminished food intake similar to that seen in genetically normal mice and rats subjected to involuntary food restriction (9). In a third instance, targeted deletion of the p66 shc signal transduction protein has been shown to lead to increased lifespan presumably mediated by increased cellular resistance to apoptosis (7).The fourth example, the Snell dwarf mutation Pit1 dw and the coallelic mutation Pit1 dwJ are the topic of...

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Section: Discussionmentioning

confidence: 99%

Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production

Flurkey

Papaconstantinou

Miller

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

770

586

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“…Third, metabolically active postmitotic cells in other tissues, such as heart, pancreas and kidney, in which cell death contributes to disease may be targets for similar therapeutic strategies, as they are likely to be subject to similar oxidative influences. Last, longevity is strongly influenced by the gradual attrition of postmitotic cells in vital organs and by the diseases that afflict them 36,48 . At advanced ages, the probability of cell death is no longer constant but increases with time, as does the risk of cancer in dividing cells.…”

Section: Targeting Antioxidants To Mitochondriamentioning

confidence: 99%

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

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We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steadystate RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.Cell death in inherited neurodegenerative disorders most commonly occurs by apoptosis 1-4 . The evidence is often indirect and inferred on the basis of characteristic morphological changes, such as chromatin compaction and cell shrinkage, or evidence of caspase activation, but in many cases it is more reliably based on multiple lines of evidence [1][2][3][4] . Caspase-independent cell death also occurs, although the precise mechanisms are less well understood and evidence that this occurs in inherited neurodegenerations is sparse. In these disorders, cell death occurs with a probability that is constant through part or all of the adult lifespan, consistent with a steady-state (one-hit or exponential kinetics) rather than a cumulative damage model 5,6 . The retina is a particularly well understood model of neurodegeneration. Mutations in more than 100 genes are known to cause neurodegeneration of retinal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell 7-9 .Two main pathways lead to the activation of cysteine proteases or caspases that execute the apoptotic death program [10][11][12] . The extrinsic pathway involves cell-surface signaling complexes (e.g., Fas or FasL), which trigger the cell death cascade by activating caspase 8 and downstream caspases. The intrinsic, or mitochondrial, pathway controls activation of caspase 9, through the adaptor molecule Apaf-1, by regulating release of cytochrome c from mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family and various stress and survival signals regulate the release of cytochrome c. Proapoptotic signals can also release proteins such as Smac and Omi, which antagonize IAP (inhibitor of apoptosis) proteins to activate cell death caspases, from the mitochondrial intermembrane space.Evidence from animal models of human photoreceptor degeneration suggests that the mitochondrial, rather than the extrinsic, cell death pa...

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“…Because of this, most of the recent increase in life expectancy has been achieved in older ages and likewise, any future increases must be fuelled by mortality reductions in the elderly population. Saving an elderly life, however, has a smaller impact on life expectancy than saving the life of a newborn, which is why life expectancy is becoming less sensitive to changes in death rates (Olshansky, Carnes & Cassel 1990). Thus, the increases in life expectancy may only continue at the present pace if death rates at older ages can be reduced much faster than in the past (Olshansky, Carnes & Désesquelles 2001).…”

Section: Pessimistic Viewmentioning

confidence: 99%

“…As already mentioned in Section 1, the rapid increase in life expectancy during the first half of the 20 th century was mainly these ages are very low and any further mortality decline will only yield small increases in life expectancy in the future (Olshansky, Carnes & Désesquelles 2001). In 1990, Olshansky and colleagues calculated that eliminating all mortality before age 50 would lead to an increase in life expectancy of only 3.5 years (Olshansky, Carnes & Cassel 1990). Because of this, most of the recent increase in life expectancy has been achieved in older ages and likewise, any future increases must be fuelled by mortality reductions in the elderly population.…”

Section: Pessimistic Viewmentioning

confidence: 99%

“…Olshansky and Ault (1986) followed by Rogers and Hackenberg (1987), without criticizing the basic premises of the theory of epidemiologic transition, introduced the idea of a fourth stage during which the maximum point of convergence of life expectancies would seem to increase as a consequence of achievements in the treatment of cardiovascular diseases (Caselli, Mesle & Vallin 2002). 4 Olshansky et al (1990) set this new maximum at 85 years, the same as that chosen by the UN (1989) for all populations in their projections at the end of the 1980s.…”

Section: The Epidemiologic Transition and Recent Changes In Mortalitymentioning

confidence: 99%

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Future Mortality in Low Mortality Countries

Caselli¹,

Drefhal²,

Wegner-Siegmundt³

et al. 2014

World Population and Human Capital in the Twenty-First Century

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Standard-Nutzungsbedingungen:Die Dokumente auf EconStor dürfen zu eigenen wissenschaftlichen Zwecken und zum Privatgebrauch gespeichert und kopiert werden.Sie dürfen die Dokumente nicht für öffentliche oder kommerzielle Zwecke vervielfältigen, öffentlich ausstellen, öffentlich zugänglich machen, vertreiben oder anderweitig nutzen.Sofern die Verfasser die Dokumente unter Open-Content-Lizenzen (insbesondere CC-Lizenzen) zur Verfügung gestellt haben sollten, gelten abweichend von diesen Nutzungsbedingungen die in der dort genannten Lizenz gewährten Nutzungsrechte. Terms of use: Documents in Future Mortality in Low-Mortality Countries AbstractThis paper provides an overview of past and expected future trends in life expectancy in experienced strong decreases in infant mortality, the future mortality trends will be driven mainly by mortality among the old and oldest-old. The paper gathers empirical background data and theoretical considerations about past and likely future determinants of mortality including smoking, obesity, biomedical progress, environmental changes and socioeconomic conditions. Based on this knowledge an internet expert survey and a metaexperts meeting were carried out to formulate expert-based assumptions for future trends in s indicate that that the positive influences on human mortality and life expectancy will likely outweigh the negative risk factors and lead to further increases of life expectancy. Moreover, the paper concludes that the differences between countries are likely to narrow further in the future.

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In Search of Methuselah: Estimating the Upper Limits to Human Longevity

Cited by 520 publications

References 30 publications

Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production

Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production

Lifespan and mitochondrial control of neurodegeneration

Future Mortality in Low Mortality Countries

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