Copyright Ó 2009 by the Genetics Society of America DOI: 10.1534/genetics.109.103341 Perspectives Anecdotal, Historical and Critical Commentaries on Genetics Edited by Adam S. Wilkins The Szilard Hypothesis on the Nature of Aging Revisited Henrik Zetterberg,*,1 Magnus Ba˚th,†,‡ Madeleine Zetterberg,§,** Peter Bernhardt†,‡ and Ola Hammarsten†† *Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, S-431 80 Mo¨lndal, Sweden, †Institute of Clinical Sciences, Department of Radiation Physics, The Sahlgrenska Academy at University of Gothenburg, S-413 45 Gothenburg, Sweden, ‡Department of Medical Physics and Biomedical Engineering, The Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden, §Institute of Biomedicine, Department of Medical Chemistry and Cell Biology, The Sahlgrenska Academy at University of Gothenburg, S-405 30 Gothenburg, Sweden, **Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation, The Sahlgrenska Academy at University of Gothenburg, S-431 80 Mo¨lndal, Sweden and ††Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at University of Gothenburg, S-413 45 Gothenburg, Sweden ABSTRACT This year marks the 50th anniversary of a nearly forgotten hypothesis on aging by Leo Szilard, best known for his pioneering work in nuclear physics, his participation in the Manhattan Project during World War II, his opposition to the nuclear arms race in the postwar era, and his pioneering ideas in biology. Given a specific set of assumptions, Szilard hypothesized that the major reason for the phenomenon of aging was aging hits, e.g., by ionizing radiation, to the gene-bearing chromosomes and presented a mathematical target-hit model enabling the calculation of the average and maximum life span of a species, as well as the influence of increased exposure to DNA-damaging factors on life expectancy. While many new findings have cast doubt on the specific features of the model, this was the first serious effort to posit accumulated genetic damage as a cause of senescence. Here, we review Szilard’s assumptions in the light of current knowledge on aging and reassess his mathematical model in an attempt to reach a conclusion on the relevance of Szilard’s aging hypothesis today. EO Szilard (born in Budapest, Hungary, 1898; died control of atomic energy out of the hands of the L in La Jolla, California, 1964) was one of the military and within a civilian department at a global leading contributors to the development of nuclear level. He joined the forces of a large number of fellow energy and the first atomic bomb. He understood the scientists and formed the Federation of Atomic Scien- concept of a nuclear chain reaction in 1933 and filed a tists, later Federation of American Scientists, which is patent for his idea the following year (Lanouette still active (http://www.fas.org/main/home.jsp). He also 1992). In 1942, with Enrico Fermi, he set up the first made efforts to encourage mutual disarmament and nuclear chain reaction. Realizing the power of what he the reduction of tensions between the United States had helped unleash, he became among the earliest and and the Soviet Union. To this end, he was active in the most active campaigners for nuclear arms control. In formation of the Pugwash Conferences on Science and spite of intense lobbying, he failed to prevent the World Affairs, together with Albert Einstein, Bertrand bombing of Hiroshima, which was a catastrophic event Russell, and others, a series of conferences concerned in his life that eventually made him leave nuclear phy- with reducing the danger of armed conflict and seeking sics (Lanouette 1992). In the postwar years, Szilard cooperative solutions for global problems (http://www. spent a major portion of his time working to place the pugwash.org/). In 1962, he helped found the Council for a Livable World, a Washington, D.C.-based lobby 1Corresponding author: Institute of Neuroscience and Physiology, De- organization for nuclear arms control, still active with the partment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, S-431 80 Mo¨lndal, Sweden. goal of providing the U.S. Congress with accurate E-mail: [email protected] technical and scientific information to facilitate bal- Genetics 182: 3–9 (May 2009) 4 H. Zetterberg et al. anced decisions about weapons of mass destruction functioning when either both chromosomes in a chro- (http://www.clw.org/). mosome pair have suffered aging hits or one of the Leo Szilard lived a nomadic life and usually had no chromosomes carries an inherited fault and the other permanent job or address (Maas and Crow 2004). one suffers an aging hit (the possibility that both chro- However, he had an enormous capacity to grasp novel mosomes in a pair carry inherited faults is neglected). For fields and erect hypotheses for others to test experimen- the female, using a single-hit, multitarget (n ¼ 2) model tally and was often acknowledged in scientific communi- for chromosome pairs without inherited faults and a cations from research groups around the world (Klein single-hit, single-target model for chromosome pairs with 1990; Lanouette 1992). After World War II, he left an inherited fault, Szilard describes the surviving fraction, nuclear physics for good and turned himself to molecular f, of somatic cells as biology, a field that had developed rapidly in the United Âà Àj 2 mÀr Àrj States under the lead of Salvador Luria, Max Delbru¨ck, f ¼ 1 ð1 À e Þ Áe ; ð1Þ and others (Klein 1990). In 1946, he accepted an where m is the number of chromosome pairs, r is the appointment as professor of biophysics at the University number of inherited faults, and j is the average number of Chicago. One of his first accomplishments was the of aging hits that have been suffered by a somatic cell at development of the Chemostat, an instrument that a given age: allows for the maintenance of bacterial populations in growth phase over an indefinite period of time by age j ¼ : ð2Þ regulating dissolved oxygen, nutrient concentrations, 2mt and pH (Novick and Szilard 1950). Experiments in the Chemostat revealed, among other things, that the t induction of the lac operon was an all-or-none phenom- In Equation 2, is the ‘‘basictime interval of the aging enon (Novick and Weiner 1957), a result fundamental process,’’ i.e., the average time interval between two to the interpretation of the data by Monod and subsequent aging hits in a somatic cell. It is assumed that t colleagues, defining the concept of negative control of is a characteristic for the species and does not vary gene expression by repressors (Pardee et al. 1958). In appreciably from individual to individual. hisNobellectureof1965(http://nobelprize.org/nobel_ Szilard continues to assume that an individual will die prizes/medicine/laureates/1965/monod-lecture.pdf), within the year in which the surviving fraction has Monod acknowledged a significant part of his Nobel reached a certain critical value, f *. The maximum life Prize to discussions with Szilard, himself never a Nobel span of a species is therefore given by the age at which an laureate. Later in life, Szilard became interested in the individual without inherited faults reaches a surviving biology of aging (Szilard 1959) and higher brain fraction of f *. To include a variation in the model, a functions (Szilard 1964). genetic scattering (stemming from an individual varia- Fifty years ago, Szilard published an article describing tion in the number of inherited faults) and a non- a mathematical target-hit model for the aging process genetic scattering (estimated from the mean age (Szilard 1959). Szilard’s model enables the calculation difference at death between identical twins) are in- of the average and maximum life span of a species, as cluded. Szilard begins by using a Poisson distribution to well as the influence of increased exposure to DNA- describe the fluctuation in the number of inherited damaging factors on the aging process. Here, we re- faults, but to simplify the mathematics he motivates the assess this largely forgotten article, scrutinize the basic use of a Gaussian distribution. Using also a Gaussian assumptions and calculations being made, describe how distribution to describe the nongenetic scattering, the model influenced the thinking about accumulated comparing the result with the actually observed distri- genetic damage as a cause of aging, and update the bution of the ages of death of the U.S. population in the mid-20th century, and assuming that the critical surviv- model on some of its most outdated assumptions. 1 ing fraction of somatic cells (f *) is 6 , Szilard ends up with an average value of r ¼ 2.5 and a value of t ¼ 6 years for humankind. Thus, using m ¼ 23, all parameters in SZILARD’S MODEL Equation 1 are known. Szilard then continues to use this Szilard’s aging model is based on a number of result to discuss various subjects such as the ‘‘physiolog- assumptions, enabling a mathematical description of ical age,’’ the effect of changing the load of inherited the aging process. The elementary step in the process is faults, and the life-shortening effect of ionizing the ‘‘aging hit’’of a chromosome, which renders all genes radiation. carried by that chromosome inactive. These aging hits are random events that have a constant probability of SZILARD’S ASSUMPTIONS occurring per unit time throughout life for a chromo- some. A chromosome may also carry an inherited fault, Szilard used the best estimates and assumptions making all its genes inactive from birth. A cell will cease from knowledge accumulated until 1958 to build his Perspectives 5 model of aging. Some of these assumptions are of a causal relation between DNA damage and aging are surprisingly close to present views, while others suffer the role of DNA as the primary informational bio- fromthefactthatlittleofthebiologyoftheDNAand molecule (Vijg 2000) and the fact that all other macro- protein machinery of the cell was known at that time.