Maximum life span
Maximum life span (or, for humans, maximum reported age at death) is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the maximum amount of time that a member of a given species could survive between birth and death, provided circumstances that are optimal to that member's longevity. Most living species have an upper limit on the number of times somatic cells not expressing telomerase can divide. This is called the Hayflick limit , although this number of cell divisions does not strictly control lifespan. Definition. In animal studies, maximum span is often taken to be the mean life span of the most long-lived 10% of a given cohort. By another definition, however, maximum life span corresponds to the age at which the oldest known member of a species or experimental group has died. Calculation of the maximum life span in the latter sense depends upon the initial sample size. "Maximum life span" contrasts with "mean life span (average life span", "life expectancy)", and "longevity". Mean life span varies with susceptibility to disease , accident, suicide and homicide, whereas maximum life span is determined by "rate of aging". Longevity refers only to the characteristics of the especially long lived members of a population, such as infirmities as they age or "compression of morbidity", and not the specific life span of an individual. In humans. Demographic evidence. The longest living person whose dates of birth and death were verified according to the modern norms of "Guinness World Records" and the Gerontology Research Group was Jeanne Calment (1875–1997), a French woman who is verified to have lived to 122. Reduction of infant mortality has accounted for  most of the increased average life span longevity, but since the 1960s mortality rates among those over 80 years have decreased by about 1.5% per year. "The progress being made in lengthening lifespans and postponing senescence is entirely due to medical and public-health efforts, rising standards of living, better education, healthier nutrition and more salubrious lifestyles." Animal studies suggest that further lengthening of median human lifespan as well as maximum lifespan could be achieved through "calorie restriction mimetic" drugs or by directly reducing food consumption. Although calorie restriction has not been proven to extend the maximum human life span  , results in ongoing primate studies have demonstrated that the assumptions derived from rodents are valid in primates. It has been proposed that no fixed theoretical limit to human longevity is apparent today. Studies in the biodemography of human longevity indicate a "late-life mortality deceleration law": that death rates level off at advanced ages to a late-life mortality plateau. That is, there is no fixed upper limit to human longevity, or fixed maximal human lifespan. This law was first quantified in 1939, when researchers found that the one-year probability of death at advanced age asymptotically approaches a limit  of 44% for women and 54% for men. However, this evidence depends on the existence of a late-life plateaus and deceleration that can be explained, in humans and other species, by the existence of very rare errors. Age-coding error rates below 1 in 10,000 are sufficient to make artificial late-life plateaus, and errors below 1 in 100,000 can generate late-life mortality deceleration. These error rates cannot be ruled out by examining documents, the standard, because of successful pension fraud, identity theft, forgeries and errors that leave no documentary evidence. This capacity for errors to explain  late-life plateaus solves the "fundamental question in aging research is whether humans and other species possess an immutable life-span limit" and suggests that a limit to human life span exists. A theoretical study suggested the maximum human lifespan to be around 125 years using a modified stretched exponential function for human survival curves. In another study, researchers claimed that there exists a maximum lifespan for humans, and that the human maximal lifespan has been declining since the 1990s. A theoretical study also suggested that the maximum human life expectancy at birth is limited by the human life characteristic  value δ, which is around 104 years. The United Nations has undertaken an important Bayesian sensitivity analysis of global population burden based on life expectancy projection at birth in future decades. The 2017 95% prediction interval of 2090 average life expectancy rises as high as +6 (106, in Century Representation Form) by 2090, with dramatic, ongoing, layered consequences on world population and demography should that happen. The prediction interval is extremely wide, and the United Nations can not be certain. Organizations like the Methuselah Foundation are working toward an end to senescence and practically unlimited human lifespan. If successful, the  demographic implications for human population will be greater in effective multiplier terms than any experienced in the last five centuries if maximum lifespan or the birthrate remain unlimited by law. Modern Malthusian predictions of overpopulation based on increased longevity have been criticized on the same basis as general population alarmism (see Malthusianism). Non-demographic evidence. Evidence for maximum lifespan is also provided by the dynamics of physiological indices with age. For example, scientists have observed that a person's VOmax value (a measure of the volume of oxygen flow to the cardiac muscle) decreases as a function of age. Therefore , the maximum lifespan of a person could be determined by calculating when the person's VOmax value drops below the basal metabolic rate necessary to sustain life, which is approximately 3 ml per kg per minute. On the basis of this hypothesis, athletes with a VOmax value between 50 and 60 at age 20 would be expected "to live for 100 to 125 years, provided they maintained their physical activity so that their rate of decline in VOmax remained constant". Longitudinal variations of physiological indices, as diverse as complete blood counts (CBC) or physical activity records collected by wearable devices , along individual aging trajectories revealed a linear increase of the organism state fluctuations range with age. The broadening could be explained by a progressive loss of physiological resilience measured by the inverse auto-correlation times of the organism state fluctuations. Extrapolation of this data suggested that organism state recovery time and variance could simultaneously diverge at a critical point of 120 – 150 years of age corresponding to a complete loss of resilience and hence should be incompatible with survival. The criticality resulting in the end of life is an intrinsic biological property of an organism that is independent of stress  factors and signifies a fundamental or absolute limit of human lifespan. The evidence of the divergence of the organism state fluctuations and hence the loss of resilience at a limiting age of approximately 130 years can also be found in the age-dependent variation of the DNA-methylation profiles obtained from human blood samples In animals. Small animals such as birds and squirrels rarely live to their maximum life span, usually dying of accidents, disease or predation. The maximum life span of most species is documented in the Anage repository. Maximum life span is usually longer for species that are  larger or have effective defenses against predation, such as bird flight, chemical defenses or living in social groups. The differences in life span between species demonstrate the role of genetics in determining maximum life span ("rate of aging"). The records (in years) are these: The longest-lived vertebrates have been variously described as Invertebrate species which continue to grow as long as they live ("e.g.," certain clams, some coral species) can on occasion live hundreds of years: In plants. Plants are referred to as annuals which live only one year, biennials which live two years, and perennials which live longer  than that. The longest-lived perennials, woody-stemmed plants such as trees and bushes, often live for hundreds and even thousands of years (one may question whether or not they may die of old age). A giant sequoia, General Sherman is alive and well in its third millennium. A Great Basin Bristlecone Pine called Methuselah is years old. Another Bristlecone Pine called Prometheus was a little older still, showing 4,862 years of growth rings. The exact age of Prometheus, however, remains unknown as it is likely that growth rings did not form every year due to the harsh environment in  which it grew but it was estimated to be ~4,900 years old when it was cut down in 1964. The oldest known plant (possibly oldest living thing) is a clonal Quaking Aspen ("Populus tremuloides") tree colony in the Fishlake National Forest in Utah called Pando at about 80,000 years. Lichen, a symbiotic algae and fungal proto-plant, such as "Rhizocarpon geographicum" can live upwards of 10,000 years. Increasing maximum life span. "Maximum life span" here means the mean life span of the most long-lived 10% of a given cohort. Caloric restriction has not yet been shown to break mammalian  world records for longevity. Rats, mice, and hamsters experience maximum life-span extension from a diet that contains all of the nutrients but only 40–60% of the calories that the animals consume when they can eat as much as they want. Mean life span is increased 65% and maximum life span is increased 50%, when caloric restriction is begun just before puberty. For fruit flies the life extending benefits of calorie restriction are gained immediately at any age upon beginning calorie restriction and ended immediately at any age upon resuming full feeding. A few transgenic strains of mice have been  created that have maximum life spans greater than that of wild-type or laboratory mice. The Ames and Snell mice, which have mutations in pituitary transcription factors and hence are deficient in Gh, LH, TSH, and secondarily IGF1, have extensions in maximal lifespan of up to 65%. To date, both in absolute and relative terms, these Ames and Snell mice have the maximum lifespan of any mouse not on caloric restriction (see below on GhR). Mutations/knockout of other genes affecting the GH/IGF1 axis, such as Lit, Ghr and Irs1 have also shown extension in lifespan, but much more  modest both in relative and absolute terms. The longest lived laboratory mouse ever was a Ghr knockout mouse, which lived to ≈1800 days in the lab of Andrzej Bartke at Southern Illinois University. The maximum for normal B6 mice under ideal conditions is 1200 days. Most biomedical gerontologists believe that biomedical molecular engineering will eventually extend maximum lifespan and even bring about rejuvenation. Anti-aging drugs are a potential tool for extending life. Aubrey de Grey, a theoretical gerontologist, has proposed that aging can be reversed by strategies for engineered negligible senescence. De Grey has established The Methuselah Mouse Prize  to award money to researchers who can extend the maximum life span of mice. So far, three Mouse Prizes have been awarded: one for breaking longevity records to Dr. Andrzej Bartke of Southern Illinois University (using GhR knockout mice); one for late-onset rejuvenation strategies to Dr. Stephen Spindler of the University of California (using caloric restriction initiated late in life); and one to Dr. Z. Dave Sharp for his work with the pharmaceutical rapamycin. Correlation with DNA repair capacity. Accumulated DNA damage appears to be a limiting factor in the determination of maximum life span. The theory that DNA  damage is the primary cause of aging, and thus a principal determinant of maximum life span, has attracted increased interest in recent years. This is based, in part, on evidence in human and mouse that inherited deficiencies in DNA repair genes often cause accelerated aging. There is also substantial evidence that DNA damage accumulates with age in mammalian tissues, such as those of the brain, muscle, liver and kidney (reviewed by Bernstein et al. and see DNA damage theory of aging and DNA damage (naturally occurring)). One expectation of the theory (that DNA damage is the primary cause of aging ) is that among species with differing maximum life spans, the capacity to repair DNA damage should correlate with lifespan. The first experimental test of this idea was by Hart and Setlow who measured the capacity of cells from seven different mammalian species to carry out DNA repair. They found that nucleotide excision repair capability increased systematically with species longevity. This correlation was striking and stimulated a series of 11 additional experiments in different laboratories over succeeding years on the relationship of nucleotide excision repair and life span in mammalian species (reviewed by Bernstein and Bernstein). In general, the findings of  these studies indicated a good correlation between nucleotide excision repair capacity and life span. The association between nucleotide excision repair capability and longevity is strengthened by the evidence that defects in nucleotide excision repair proteins in humans and rodents cause features of premature aging, as reviewed by Diderich. Further support for the theory that DNA damage is the primary cause of aging comes from study of Poly ADP ribose polymerases (PARPs). PARPs are enzymes that are activated by DNA strand breaks and play a role in DNA base excision repair. Burkle et al. reviewed evidence that PARPs, and especially PARP-1 , are involved in maintaining mammalian longevity. The life span of 13 mammalian species correlated with poly(ADP ribosyl)ation capability measured in mononuclear cells. Furthermore, lymphoblastoid cell lines from peripheral blood lymphocytes of humans over age 100 had a significantly higher poly(ADP-ribosyl)ation capability than control cell lines from younger individuals.