The Quest for the General Theory of Aging and Longevity Leonid A. Gavrilov Natalia S. Gavrilova Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL 60637

Aging is a Very General Phenomenon!

Naive but important question on the origin of aging: How to explain aging of the system built of non-aging elements? This question is important for understanding the systemic component of aging (aging of the system as a whole) because: Many aging theories are "explaining" aging of the system through aging of its components. However, this circular reasoning of assuming aging in order to "explain" aging leads us to a logical blind alley, because moving in succession from the aging of the organism to the aging of organs, tissues and cells, we eventually come to atoms, which are known not to age. Thus, the key to the explanation of aging is the question: How do we explain the aging of a system constructed out of non-aging components?

What Should the Aging Theory Explain: Why do most biological species deteriorate with age? Specifically, why do mortality rates increase exponentially with age in many adult species (Gompertz law)? Why does the age-related increase in mortality rates vanish at older ages (mortality deceleration)? How do we explain the so-called compensation law of mortality (Gavrilov & Gavrilova, 1991)?

Compensation Law of Mortality Convergence of Mortality Rates with Age 1 – India, , males 2 – Turkey, , males 3 – Kenya, 1969, males 4 - Northern Ireland, , males 5 - England and Wales, , females 6 - Austria, , females 7 - Norway, , females Source: Gavrilov, Gavrilova, “The Biology of Life Span” 1991

Mortality at Advanced Ages Source: Gavrilov L.A., Gavrilova N.S. The Biology of Life Span: A Quantitative Approach, NY: Harwood Academic Publisher, 1991

M. Greenwood, J. O. Irwin. BIOSTATISTICS OF SENILITY

Redundancy Creates Both Damage Tolerance and Damage Accumulation (Aging)

Why Organisms May Be Different From Machines?

Differences in reliability structure between (a) technical devices and (b) biological systems

Mortality Kinetics in Highly Redundant Systems Saturated with Defects Failure rate of a system is described by the formula: where n is a number of mutually substitutable elements (connected in parallel) organized in m blocks connected in series; k - constant failure rate of the elements; i - is a number of initially functional elements in a block; λ - is a Poisson constant (mean number of initially functional elements in a block). Source: Gavrilov L.A., Gavrilova N.S. The reliability theory of aging and longevity. Journal of Theoretical Biology, 2001, 213(4):

Dependence of the logarithm of mortality force (failure rate) on age for binomial law of mortality

Conclusions (I) REDUNDANCY is a key for understanding aging and the systemic nature of aging in particular: Systems, which are redundant in numbers of irreplaceable elements will always deteriorate (age) over time, even if they are built of non-aging elements. Apparent aging rate or expression of aging (age differences in failure rates, including death rates) is increasing with higher redundancy levels. REDUNDANCY EXHAUSTION over the life course is responsible for the "compensation law of mortality" (mortality convergence at later life) as well as for the "late-life mortality deceleration, levelling-off and mortality plateaus" Organisms seems to be formed with high LOAD OF INITIAL DAMAGE and, therefore, their lifespan and aging patterns may be sensitive to EARLY-LIFE CONDITIONS, which determine this initial damage load during early development. Implications: potentially great opportunities for anti-aging interventions if started extremely early (before birth?).

Conclusions (II) Aging studies should not be limited to the studies of qualitative changes (like age changes in gene expression), because changes in QUANTITY (numbers of cells and other functional elements) could be the driving force of aging process. Aging may be driven by a process of redundancy loss. Lifespan is not fixed -- there is no absolute specific limit to the duration of life. Limits are in our minds only. SUGGESTION: It is important to demystify aging and to begin considering it as not a mysterious and immutable process, but rather as a collection of destruction pathways, many of which are already known as pathways for specific age-related degenerative diseases. Therefore, separation of aging and diseases is worthless and counter-productive.

Acknowledgments This study was made possible thanks to: generous support from the National Institute on Aging, and stimulating working environment at the Center on Aging, NORC/University of Chicago