In an effort to identify and understand fundamental mechanisms of aging, we screened for changes that occur in the organelles of replicatively aging “mother” cells of the budding yeast, S. cerevisiae. In this screen we identified key changes, including an age-dependent accumulation of lipid droplets (LDs) as shown by staining of LDs and fluorescent tagging of known LD proteins. Classically, LDs are storage sites for energy in the form of neutral lipids (NLs) and therefore play important roles in energy metabolism and lipid-based signaling. To begin to understand the genetic network that underlies LD accumulation during aging, we carried out semi-targeted gene mutation analysis and screened for delays in the age of onset of LD accumulation. Surprisingly, deletion and/or overexpression (OE) of genes known to affect LDs had minor effects on LD accumulation during aging. In fact, deletion of only one of the four acyltransferases that synthesize triacylglycerol, the major NL of LDs, suppressed LD accumulation during aging. These data suggest that a limited number of biosynthetic pathways underlie LD accumulation during aging. Age-associated LD accumulation was also delayed by deletion of Longevity Assurance Gene 1, which encodes the founding eukaryotic ceramide synthase; interestingly, LAG1 was the first gene ever described that when deleted extends the lifespan of an organism (D’mello et. al. JBC 1994). These data suggest a role for sphingolipids in LD accumulation and correlates increased LDs with reduced lifespan. Furthermore, LD accumulation during aging was delayed by OE of the conserved and rate-limiting enzyme of the pathway for nicotinamide adenine dinucleotide (NAD+) biosynthesis. Because NAD+ levels have been shown to decline during aging in eukaryotes, our data suggests that the age-dependent accumulation of lipid droplets is influenced by the age-dependent decline in the levels of NAD+. The levels of NAD+ are regulated in yeast by processes such as biosynthesis, NAD+ dependent histone deacetylases (i.e., sirtuins), the salvage pathway, and the repertoire of NAD+ dependent metabolic reactions occurring at any given time. Lastly, we investigated whether LD accumulation during aging was sensitive to genetic manipulation of the processes that regulate NAD+ levels and to treatment with vitamin precursors of NAD+. We found that perturbations expected to increase NAD+ levels delayed/reversed age-associated LD accumulation, which suggests that the metabolic circuitry of old cells can be manipulated in ways that alleviate LD accumulation. We are now determining which NAD+ dependent metabolic processes influence NL metabolism with age and how those changes affect energy metabolism and lifespan. We speculate that our studies are relevant to the widespread obesity problem and its impact on the aging process and disease.