Supplement 9-1

1. Supplement 9-1 The following slides present data which supports the views taken in Figures 9-4 and 9-6 of the textbook. These data present empirical evidence supporting 1) the existence of modifier or minor effect genes, 2) the fact that they outnumber the major effect genes, and 3) the important role they play in modulating the action of the major effect genes. They also illustrate the synergistic negative effect that low levels of abnormal proteins may have on the individual organism via their acting at the post-translational level to disrupt protein folding, clog up the protein disposal systems, and generally raise havoc with many of the cell’s mechanisms. The result is a loss of cell function and eventual death.

2. Let us start with the evidence for hsp involvement in longevity Both HSF & ISP are required for extended longevity

3. hsf in muscle tissue extends life span hsf in neural or intestinal tissue also extends life span

4. Ex. 2 ts Mutations With Low Effect Act As Significant Modifiers of PolyQ Genes in Caenorhabiditis Pre-existing abnormal proteins synergistically enhance the effects of other abnormal proteins, & accelerate onset of senescence From Gidalevitz et al. Science 311:1471, 2006

5. MnSOD Deficiency in Mice is a Monogenic Trait Significantly Modified by Other Genes Survival of short lived strain + 1 QTL from long lived strain (#116.1 on next slide) Survival of short-lived strain Survival of F1 hybrid strain Huang et al, Hum. Mol. Gen. 15:1187, 2006

6. MnSOD Effects Are Modified By The mt-NNT Gene on the Same Chromosome *

7. Huang et al, Hum. Mol. Gen. 15:1187, 2006 NNT is postulated to modify the effects of MnSOD deficiency due to NNT’s ability to decrease the internal ROS levels in the mitochondria, and thus decrease the rate of increase of mt ROS. NNT = nicotinamide nucleotide transhydrogenase

8. Ex. 1 MnSOD Deficiency in Mice is a Monogenic Trait Significantly Modified by Other Genes But these data only explain the C57BL/6J – DBA/2J difference in this one QTL. They do NOT explain the extra difference between DBA/2J and B6D2F1. To explain those differences, you must postulate the existence of additional modifier genes. Thus the number of modifier genes is at least 2 (and probably 5). Thus the # of modifier genes > # of major genes. What does that inequality mean from the viewpoint of genetic architecture? Huang et al, Hum. Mol. Gen. 15:1187, 2006

9. What does that inequality mean from the viewpoint of genetic architecture? It means that modifier genes exist for both the ADS genes & for hsps. There are more modifier genes than major genes. The modifier genes can cause synergistic effects in enhancing or decreasing cell function. BUT, if the modifier genes are so potent, then how is it that certain Tx can bring about systemic effects?

10. Reducing I-IGF &/or dFOXO Signaling Halts Cardiac Aging in Flies… heart rate heart failure rate …But Cardiac Aging Can Be Restarted by Excess JH which is itself regulated by dFOXO from Wessels et al., Nature Genetics 36:1275, 2004

11. FOXO3a Levels & Senescence Are Causally Connected in Human Fibroblasts in vitro from Kim et al., JGBS 60A:4-9, 2005

12. HDAc-Inhibitors Work in Flies Drug Interventions Extend Longevity in Flies The HDAcs specifically induce many stress-resistance genes. The Drug Activates the Fly’s Stress Resistance Genes Glucoregulatory drugs extend longevity in rats. (Spindler et al., 2004) from Kang et al., PNAS 99 (2):838, 2002

13. Old Animals Have Lower Levels of Signals Than Do Young Animals…But Their Cells Are Still Responsive Cells from Old Animals Put in Culture and Bathed with Sera from Young Animals Have Higher Incidence of Activated Regenerating Cells Than Do Old Cells in Old Sera. Pair Old or Young Animals via Common Circulatory System….. Measure Their Ability to Regenerate Damaged Muscle. Old Animals Regenerate Better When They Have Young Blood Circulating! Old Cells Are Activated to Regenerate By Sera From Young Animals! Aging May Be A Software Problem & Not A Hardware Problem! from Conboy et al., Nature 433:760, 2005

14. The Transition from Health to Senescence is Regulated by Major & Minor Genes Acting at the Cell Level And what about the minor effect genes, & what do they have to do with a “gene interaction network”? JH ---------l from Arking, 2005, based on work from the Morimoto lab

15. Senescence May Start With the Degradation of the Gene Interaction Network 1 2 hubs & spokes 4 3 6 5 after Giot et al, 2003