Middle Age Has Its Advantages

If we’re lucky, we get old. Physical and mental decline are negative hallmark associations of aging. Imagine being born blind and, as you approach middle age, waking up with the ability to see. In this issue of PLOS Genetics, Cornils, Maurya, and colleagues discover such a phenomenon: age-related suppression of ciliogenesis defects [1]. Cilia are microtubule-based organelles that protrude from most nondividing cells in the human body. Pathologies in cilia formation or function result in human ciliopathies with broad clinical manifestations, including sensory defects, developmental abnormalities, cystic kidneys, infertility, and cancer. Based on the frequency of polycystic kidney disease alone, ciliopathies affect at least 1 in 800 individuals. Hence, identifying a way to recover ciliary function in these patients would have a profound impact. Our fundamental understanding of ciliogenesis is based on seminal research in Chlamydomonas and Caenorhabditis elegans [2–6]. Intraflagellar transport (IFT) constructs all cilia and flagella [7]. Anterograde kinesin-2 and retrograde dynein motors transport the multi-protein IFT-A and IFT-B complex machinery and associated cargo along the microtubule-based ciliary axoneme. In Chlamydomonas and C. elegans, mutations in the IFT motors or the IFT machinery result in flagella-less algae or cilia-less worms, respectively. In mice and humans, null mutations in IFT genes are lethal, whereas non-null mutations can produce ciliopathies. Many of the genes required for the formation, specialization, and sensory properties of C. elegans cilia have human counterparts that, when mutated, cause ciliopathies [6,8,9]. Unlike mice or humans, worms lacking cilia are viable and fertile under laboratory conditions but exhibit severe sensory defects. Cornils, Maurya, and colleagues performed physicals of middleaged worms, examining channel cilia of amphid sensory neurons found in the worms’ heads. Shockingly, with age, some previously cilia-less IFT mutants grew functional cilia! The average life expectancy of a wild-type C. elegans adult is approximately 12 to 18 days. Age-dependent ciliary recovery (AdCR) of certain IFT mutants occurs between 4 to 7 days of adulthood. AdCR is observed only in hypomorphic, but not null, alleles of C. elegans IFT-A or IFT-B component genes. These non-null hypomophic alleles include splice site, in-frame deletion, and premature nonsense mutations that have no physiological activity in larval stages and early adulthood. As a consequence, juvenile and young adult mutant animals have stunted and nonfunctional cilia. However, in middle age, IFT-A or IFT-B hypomorphs extend cilia, albeit not to wild-type lengths. Visualization of cilia with in vivo cell-specific reporters reveals AdCR in multiple cilia types, suggesting that, with age, all cilia have the potential to recover from an inherited genetic insult. Ultrastructural analysis using transmission electron microscopy confirms that age-recovered cilia possess both proximal and distal axonemal regions. AdCR is transient—after 7 days of adulthood, cilia are lost. In wild-type C. elegans amphid channel cilia, two kinesin-2 motors drive IFT. The slower kinesin-II and faster homodimeric OSM-3/KIF17 act redundantly to construct the proximal