Asymmetric cell division is key to cellular differentiation and cell renewal. For example, the budding yeast Saccharomyces cerevisiae utilizes asymmetrical division to generate a young daughter cell from a mother cell that grows progressively older with each cell division and finally perishes; the hallmark of replicative aging. This singular division event provides a tractable model for how age physiognomies are reset in the progeny and show that the generation of a pristine daughter cell requires asymmetrical segregation and compartmentalization of cytoplasmic ‘aging factors’. Identification of such aging factors is one of the ‘holy grails’ of gerontology as this might provide clues towards therapeutically halting, or even reversing, senescence and tissue decline. Aberrant and aggregated proteins have been suggested to act as aging factors in budding yeast and candidate approaches have revealed that the protein remodeling factor Hsp104, the anti-aging protein Sir2, the actin cytoskeleton, and actin polarity machinery are required for this asymmetrical inheritance of such aggregated proteins. We have now used high-content-analysis (HCA) combined with synthetic genetic array (SGA) technology in a systematic, genome-wide screen for genes required for protein inclusion body (IB) formation, aggregate recognition by chaperones, and asymmetric aggregate inheritance. Apart from requiring members of the polarity machinery, deposition and segregation of IBs involve key factors involved in vesicle transport and tethering to specific organelles, including the vacuole. Moreover, blocking IB formation by diminishing vesicle tethering rendered some misfolded proteins severely toxic. We also found that the overproduction of some unconventional players involved in aggregate recognition and clearance, including the Mca1 metacaspase, drastically extended mother cell lifespan suggesting that protein aggregates act as bona fide aging factors.