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Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved

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Abstract

Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)). In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading. Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body’s primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.

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Notes

  1. Gilpin, M. (1975) Group Selection in Predator-Prey Communities, Princeton University Press, https://doi.org/10.2307/j.ctvx5wbvr.

  2. Hypermethylated and hypomethylated should not be confused with type (1) and type (2). These ways of categorizing CpG sites are independent and cut across each other.

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    Josh Mitteldorf

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Mitteldorf, J. Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved. Biochemistry Moscow 89, 356–366 (2024). https://doi.org/10.1134/S0006297924020135

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