Mechanisms determining both functional rate of decline and the time of onset in aging remain elusive. Studies of the aging process especially those involving the comparison of long-lived individuals and young controls are fairly limited. Therefore, this research aims to determine the differential gene expression profile in related individuals from villages in Pahang, Malaysia. Genome-wide microarray analysis of 18 samples of peripheral blood mononuclear cells (PBMCs) from two groups: octo/nonagenarians (80–99 years old) and their offspring ( years old) revealed that 477 transcripts were age-induced and 335 transcripts were age-repressed with fold changes ≥1.2 in octo/nonagenarians compared to offspring. Interestingly, changes in gene expression were associated with increased capacity for apoptosis (BAK1), cell cycle regulation (CDKN1B), metabolic process (LRPAP1), insulin action (IGF2R), and increased immune and inflammatory response (IL27RA), whereas response to stress (HSPA8), damage stimulus (XRCC6), and chromatin remodelling (TINF2) pathways were downregulated in octo/nonagenarians. These results suggested that systemic telomere maintenance, metabolism, cell signalling, and redox regulation may be important for individuals to maintain their healthy state with advancing age and that these processes play an important role in the determination of the healthy life-span. 1. Introduction The aging process determined by genetic and environmental factors remains unchanged despite increasing the average life-span of the general population in recent decades [1]. The heritability component of human longevity ranged from 20% to 30% and can increase to about 50% after the age of 60 [2]. Thus, the search for genes affecting longevity in humans was mostly conducted on subjects at an advanced age involving centenarians. Families living such extremely long lives perhaps possess genetic variations that affect either the rate of aging or genes that result in decreased susceptibility to age-associated diseases [1]. Identification of innate genes that changes in expression with age, in a small population to minimize variations arising from environmental factors such as diet and lifestyle, can be useful as targets for intervention or can be used as biomarkers of aging. Uncovering interactions of major regulatory pathways and targets is crucial to elucidate aging mechanisms. Some of the most promising candidate genes appear to be involved in regulatory pathways such as stress resistance, immune/inflammatory response, insulin signalling, or cardiovascular function. Such
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