A review proposed an experiment to separate the role of mutations in aging from the role of DNA damage signaling
A review proposed an experiment to separate the role of mutations in aging from the role of DNA damage signaling
On August 26, Lucrezia Trastulla and Fabrizio d’Adda di Fagagna published a review in Aging comparing cellular senescence, a state in which a cell stops dividing for an extended period after stress, with somatic mutations that arise in the body’s cells. The authors assess both processes using experiments that distinguish causes of age-related dysfunction from features that merely become more common with age.
A somatic mutation alters the DNA of a single cell. If that cell begins to proliferate more rapidly, it can produce a clone, which is a group of cells carrying the same mutation. This process creates genomic mosaicism in tissues. DNA damage activates protective signaling and repair within the cell. An error during repair can leave a mutation behind.
“When DNA damage occurs, what drives aging: the associated signaling response or the mutations that can result from inaccurate repair?”
For cellular senescence, the authors cite experiments testing both necessity and sufficiency. In experiments involving mice with modified genes, researchers removed cells expressing p16Ink4a, one of the markers of senescence. Sarcopenia, meaning loss of muscle mass, cataracts, and lipodystrophy, meaning loss of adipose tissue, developed later or were less severe in these animals. When researchers injected fewer than one million senescent cells into young mice, the animals’ physical function declined. Removing the cells tests whether they are required for age-related dysfunction, while introducing them tests whether they can cause it.
Senescent cells secrete SASP, a group of substances that sustain inflammation, alter the environment between cells, and can induce the same state in neighboring cells. Through these effects, a small population of cells can impair tissue function.
People with inherited defects in the proofreading activity of DNA polymerases ε and δ, the enzymes that copy DNA, have more mutations in normal cells. No signs of premature aging have been identified in these individuals. In several models of accelerated aging, suppressing p53, a protein that activates the cellular response to DNA damage, reduced age-related dysfunction even though the telomeres, the terminal regions of chromosomes, remained critically short. In these models, this result supports a role for the damage signal itself. In an experiment targeting telomere damage signaling, Fabrizio d’Adda di Fagagna’s group improved hematopoietic recovery in mice without lengthening their telomeres.
To test the role of the mutations themselves, the authors propose generating many base substitutions, which replace individual DNA “letters,” while causing as little damage as possible to the DNA molecule. Base editors may be suitable because they replace a letter without cutting both DNA strands. Any residual damage signaling in such an experiment would need to be measured separately. Tracking the descendants of individual cells, together with measurements of gene activity and other molecules in the tissue, would allow researchers to compare mutation burden and clone size with impaired tissue function. The authors propose using this approach to assess separately how altered DNA sequences and DNA damage signaling contribute to age-related dysfunction.