Baker INK-ATTAC experiment

Background

Cellular senescence arrests damaged cells and suppresses tumor formation, and senescent cells accumulate in tissues with age. The Serrano–Lowe experiment had shown that p16 and p53 enforce an oncogene-induced arrest, and p16 expression became the standard marker for senescent cells in tissue.³ The accumulation of p16-positive cells correlated with age-related disease, and the correlation left open whether the cells cause the pathology or merely accompany it. A causal test required a way to eliminate the cells on demand in a living animal.

Design

The INK-ATTAC transgene places a fragment of the p16 promoter in front of an inducible suicide system: a fusion protein that triggers apoptosis when the drug AP20187 is supplied. Because the promoter drives the construct, AP20187 kills cells that express p16 at the time of treatment. The 2011 study introduced INK-ATTAC into a BubR1 hypomorphic strain, a progeroid model with accelerated age-related phenotypes, and compared lifelong clearance with clearance started later in life. The 2016 study used wild-type mice of two genetic backgrounds, began AP20187 treatment at one year of age, and dosed twice weekly while tracking survival and organ function.¹²

Result

In the progeroid strain, INK-ATTAC removed p16-positive cells from adipose tissue, skeletal muscle, and eye, and lifelong clearance delayed the onset of the associated pathologies. Late-life clearance attenuated the progression of disorders that had already developed, which showed that the cells act on established tissue dysfunction as well as on its initiation. In normal mice, clearing p16-positive cells extended median lifespan in both male and female animals of two genetic backgrounds. The treatment also delayed tumorigenesis and preserved kidney glomeruli, cardiac KATP channels, and fat-cell function.¹²

What it established

The two experiments carry separate conclusions, a distinction the pair is often collapsed into:

• The 2011 study showed that p16-positive cells contribute causally to age-related pathology, using a progeroid background in which those phenotypes are accelerated.
• The 2016 study showed that naturally accumulating p16-positive cells shorten lifespan and degrade organ function in ordinary aging, and that their removal extends median lifespan.

The work supplied the biological rationale for senolytics, drugs that selectively kill senescent cells, and it made p16-positive cell burden a target for intervention. It also tied the Hayflick–Moorhead phenotype and the oncogene-induced senescence program to organismal aging, and it placed senescent cells among the mechanisms discussed in the tumor suppressor theory of aging.

Limits and later work

The transgene labels cells by p16 expression, a population that includes senescent cells alongside other cell states, and the promoter fragment captures a subset of p16 activity. Killing these cells throughout life removes any protective functions they carry in tumor suppression and wound healing, so the long-term balance of clearance depends on which cells and tissues are affected. The lifespan result came from mice under laboratory conditions, and extending it to human aging requires senolytic drugs with acceptable selectivity, which later studies pursued with combinations such as dasatinib and quercetin. The distinction between the progeroid 2011 result and the normal-aging 2016 result remains the key qualification when the experiments are cited.

See also

• p16^INK4a (CDKN2A)
• Cellular senescence
• Types of cell senescence and quiescence
• Tumor suppressor theory of aging
• History of biogerontology

References