Telocyte Newsletter, Q4 2023: Which Piece is the Elephant?

In the traditional story, the blindmen each thought they knew what an elephant was, yet each of them knew only pieces of the elephant: the trunk, the ear, the tusks, the legs, the flank, the tail. Elephants aren’t pieces, they are whole creatures.

It’s a lesson we seldom ever learn completely. To the contrary, we often mistake biomarkers as the equivalent of aging, as in recent books purporting to explain longevity and aging, or in the global conferences I have had the pleasure to chair. In each case, we slip into the error of – at worst – thinking a piece of the elephant is an elephant (is an elephant ear an elephant or is it a pastry?) or – at best – thinking that if we can just sew all the pieces together, we’ll have a live elephant (or is it a Frankenstein in need of a lightning bolt?).

It’s not the elephant that requires lightning to come alive: it’s our understanding that requires enlightening to understand life.

Biomarkers and clinical findings are not the same as aging. If, for example, we think that mitochondrial dysfunction causes aging, then what causes mitochondrial dysfunction? If immune dysfunction causes aging, then what causes immune dysfunction? Too often, these questions go unanswered. The purveyors of books and nostrums recommend a piecemeal approach: they would treat the elephant’s ear with nutrition, the elephant’s trunk with exercise, the elephant’s leg with improved sleep, the elephant’s flank with emotional support, and the elephant’s tail with tales of mental health. What about the elephant?

These approaches are naïve reductionism and miss the point: elephants are whole living systems; aging is a complex living process and not merely a collection of biomarkers. You may live longer if you eat right and exercise, but you will not reverse the aging process anymore than you can reassemble a living elephant by sewing ears to legs or trunks to tails. We can only alter aging if we look at the entire conceptual elephant.

The same is true of the diseases of aging. For the past two decades, we have slipped into the wishful simplicity of viewing Alzheimer’s as a disease of beta amyloid, hence the vogue of monoclonal antibody therapies aimed at this target. Amyloid is a prominent player in Alzheimer’s, just as the trunk is a prominent part of an elephant. Amyloid is a typical biomarker of Alzheimer’s, but is not the entire disease; trunks are typical of elephants, but are not the entire elephant.

Small wonder that the results of monoclonal antibody therapies are only arguably effective (or safe). As Dr. Russell Swerdlow recently suggested¹, even if monoclonal antibodies clear the amyloid plaque, it may be that “the disease is still progressing. …until we truly fully understand how the disease starts… we don’t know what’s disease-modifying or not.” Amyloid may play a role, but causation is another matter. Recent editorials² have echoed this concern, pointing out that the clinical data supporting the use of monoclonal antibodies targeting amyloid are not particularly different from the data supporting the use of symptomatic therapies, such as Aricept. We won’t cure Alzheimer’s by randomly targeting biomarkers, anymore than we could cure Covid by randomly targeting its symptoms.

We can only cure Alzheimer’s if we take a sincere look at the elephant.

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¹ Rubin R. Who Should—and Can—Get Lecanemab, the New Alzheimer Disease Drug? JAMA, September 27, 2023. https://doi.org/10.1001/jama.2023.14443

² Molchan S, Fugh-Berman A. Are New Alzheimer’s Drugs Better than Older Drugs? JAMA Int Med, 2023;183:902-903. https://doi.org/10.1001/jamainternmed.2023.3061