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

Area of Science:

• Gerontology
• Epigenetics
• Molecular Biology

Background:

• Aging involves a programmed self-destruction (phenoptosis) driven by epigenetic changes.
• Two types of epigenetic changes occur: type (1) promotes self-destruction, while type (2) responds to damage for survival.
• Epigenetic clocks offer rapid assessment of anti-aging interventions but currently fail to differentiate between these two types of epigenetic changes.

Purpose of the Study:

• To highlight the limitations of current epigenetic clocks in distinguishing between lifespan-extending and lifespan-shortening epigenetic modifications.
• To propose the necessity of separating type (1) and type (2) epigenetic changes for accurate biological age assessment.
• To suggest that epigenetic changes are mechanisms, not the primary timekeepers of aging.

Main Methods:

• Critically analyze the existing literature on epigenetic clocks and their application in aging research.
• Propose new experimental designs to differentiate between type (1) and type (2) epigenetic changes.
• Discuss the potential role of the hypothalamus as a biological timekeeping mechanism.

Main Results:

• Existing epigenetic clocks may be misleading because they do not distinguish between type (1) and type (2) epigenetic changes.
• Reversing type (1) epigenetic changes can extend lifespan, whereas reversing type (2) can shorten it.
• Epigenetic changes implement phenoptosis but are not the primary biological clock.

Conclusions:

• Accurate measurement of biological age requires distinguishing between distinct types of epigenetic changes.
• Future anti-aging interventions should target the fundamental biological clock, not solely epigenetic markers.
• The primary timekeeping mechanism of aging remains to be fully elucidated, with potential links to the hypothalamus.