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Undoing Aging with Molecular and Cellular Damage Repair

Since the dawn of medicine, aging has been doctors’ foremost challenge.

Since the dawn of medicine, aging has been doctors’ foremost challenge. Three unsuccessful approaches to conquering it have failed: treating components of age-related ill health as curable diseases, extrapolating from differences between species in the rate of aging, and emulating the life extension that famine elicits in short-lived species. SENS Research Foundation is spearheading the fourth age of anti-aging research: the repair of age-related damage, that is, rejuvenation biotechnology.

The Strategies for Engineered Negligible Senescence (SENS) approach was first proposed in 2002. “Senescence,” here, refers to the actuarial phenomenon—the trend that individuals within a population suffer from an increasing morbidity and mortality rate in (typically exponential) relation to their chronological age. “Negligible” is used in a statistical sense: we consider a level of senescence negligible if no age-related contribution to mortality is statistically demonstrable within a population, given the “background noise” of age-independent mortality (such as unfortunate encounters with motor vehicles). Finally, by “Engineered,” we indicate that this state is achieved by the deliberate application of biomedical therapies, and is not the normal situation. The goal of SENSE is thus unambiguously defined; we seek methods to convert a population experiencing a non-negligible level of senescence into one experiencing a negligible level.

To see how the goal of negligible senescence could be “engineered,” it is useful to consider a situation in which human ingenuity and perseverance has already achieved an analogous result. Motor vehicles experience a process of wear-and-tear essentially similar to organismal aging; the paint flakes, windowpanes chip, rust infiltrates the pipework, and so forth. Nonetheless, as vintage car owners will attest, it is entirely possible to keep one functional for an essentially indefinite period. Critically, this is achieved not by preventing the wear but by repairing the damage that does occur at a rate sufficient to ensure that the function of the machine is never irretrievably compromised.

Of course, the analogy is inexact; human bodies are far more complex than cars but a closer look at precisely how growing older leads to debility reveals that our ignorance need not be showstopping.

Aging can be characterized as a three-stage process. In the first stage, metabolic processes essential to life produce toxins. Secondly, a small amount of the damage caused by these toxins cannot be removed by the body’s endogenous repair systems, and consequently accumulates over time. In the third stage, the accumulation of damage drives age-related pathology.

Undoing Aging with Molecular and Cellular Damage Repair

This model—metabolism causes damage causes pathology—allows us to clarify the requirements for successful intervention in aging. Unlike the dynamic processes of metabolism and pathology, accumulated damage represents a relatively stationary target. That is to say, it may not be clear whether a given type of damage is pathological (on balance), but its absence from healthy twenty-year-olds indicates that it is not required for healthy life. Conversely it is clear that the total ensemble of types of damage is pathological, since fifty-year-olds have considerably less time to live than twenty-year-olds, and the only static difference between the two groups is the amount of accumulated damage present.

Accepting the implications of this model leads us to the SENS approach; by identifying and repairing all of the damage accumulated during aging, we can restore the body to a youthful state. Consequently, its dynamic metabolic processes will revert to their own norms, and the risk of mortality will be no higher than in any other equivalently “youthful” individual—whether they have actually lived for twenty years or 120. Furthermore—so long as our inventory of damage classes is sufficiently comprehensive—we can repeat this effort on a regular basis, and thus remain indefinitely below the threshold of pathology. Crucially, we can do this without a comprehensive understanding of the complex metabolic processes giving rise to damage, nor of those leading from damage to pathology. We need only an inventory of the types of damage which exist, which can be obtained directly by comparison of older and younger individuals. And, fortunately, it seems that all aging-related damage known to accumulate in the human body can be classified into just seven clearly defined categories: cell loss, cell death-resistance, cell over-proliferation, intracellular and extracellular “junk”, tissue stiffening and mitochondrial defects.

SENS is a hugely radical departure from prior themes of biomedical gerontology, involving the bona fide reversal of aging rather than its mere retardation. By virtue of a painstaking process of mutual education between the fields of biogerontology and regenerative medicine, it has now risen to the status of an acknowledged viable option for the eventual medical control of aging and its credibility will continue to rise as the underlying technology of regenerative medicine progresses.

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