In the spring of 1512, three wooden vessels commanded by the Spanish explorer Ponce de León left the warm Caribbean waters off Puerto Rico in search of the fountain of youth. Fuelled by his desire for immortality, Ponce de León was convinced that drinking from this legendary spring would confer a state of eternal youth. Local legend suggested that the fountain could be found in the lands to the north and that it was surrounded by magnificent flowering plants. Over the next few months, the explorers travelled from island to island, tasting rivers and lakes (Fig. 1) until short supplies and hostile natives forced them to abandon their quest.
Figure 1: A quest for longevity.
Five hundred years ago, the Spanish explorer Ponce de León drank his way around the Florida coast during his expedition to find the legendary fountain of youth.
High resolution image and legend (102K)Today, the once desolate shores of Florida — the 'land to the north' that Ponce de León discovered inadvertently on his voyage — are crowded with ageing retirees who yearn just as passionately for the magical elixir of youth. Although the past two decades have seen an explosion in our understanding of the molecular regulation of ageing, a simple potion or chemical that could slow the ageing process seems as elusive today as it was 500 years ago. But on page 191 in this issue, Howitz et al.1 present a study of longevity in yeast that could represent the first step towards creating such a hypothetical elixir.
It is well established that reducing food intake (caloric restriction) extends lifespan in a wide range of species2. But given the current epidemic of obesity in industrialized societies, eating less for the sake of longevity is not likely to gain widespread compliance. More palatable would be a drug that could mimic the effects of caloric restriction — a chemical that would allow the individual to eat normally, while tricking the body to respond as though food were in short supply. Such mimetics might be thought of as the pharmaceutical equivalent of 'eating your cake without having it'.
Studies of longevity in simple organisms have greatly expanded our understanding of how caloric restriction might increase lifespan. In the budding yeast Saccharomyces cerevisiae, nutrient withdrawal extends longevity through a pathway that requires the enzyme Sir2 (ref. 3). Overproducing this enzyme can prolong the life of yeast grown under normal nutrient conditions4. Similarly, in the evolutionarily more advanced worm Caenorhabditis elegans, increased expression of the worm's version of Sir2 has also been shown to extend lifespan5.
The Sir2 enzyme belongs to a large family of evolutionarily conserved molecules termed sirtuins. In lower organisms, such as yeast and worms, these enzymes regulate a wide range of cellular activities that affect lifespan, including modulating how tightly DNA is packaged inside cells. In mammalian cells, sirtuins act as regulators of programmed cell death and differentiation (cell maturation)6. Sirtuins exert their effects on these cellular processes by removing acetyl groups from specific target proteins. Interestingly, this 'deacetylase' function depends on the intracellular concentration of a molecule involved in metabolism — nicotinamide adenine dinucleotide (NAD). This molecule can exist in two states, oxidized and reduced, and it is the oxidized form that greatly enhances Sir2 activity. It seems that in yeast, caloric restriction may regulate Sir2 activity, and hence prolong life, by subtly shifting the ratio of oxidized to reduced NAD or by altering the level of the NAD derivative nicotinamide7, 8. Together, these findings suggest a potential mechanism by which metabolic activity and lifespan might converge (Fig. 2).
Figure 2: The pathway to long life.
When yeast cells are deprived of food (caloric restriction), stress pathways are activated and the cells are forced to derive energy from alternative substrates. This produces alterations in oxygen consumption, which in turn affects the ratio of oxidized to reduced forms of nicotinamide adenine dinucleotide (NAD:NADH) or the concentration of its derivative nicotinamide. NAD stimulates the activity of Sir2, which in turn chemically modifies several proteins that are involved in cellular processes affecting longevity. Howitz et al.1 have found that plant polyphenols directly activate Sir2 and seem to mimic the beneficial effects of food restriction. Related pathways may exist in higher organisms.
High resolution image and legend (58K)Building on the knowledge that caloric restriction prolongs longevity through Sir2, Howitz et al.1 searched for a small molecule that could activate this enzyme directly. Using several chemical 'libraries', these investigators discovered two related compounds that each stimulated Sir2 activity. Both compounds belong to a family of molecules called polyphenols — products of metabolism in plants. One of the most widely studied of these compounds is resveratrol, a plant polyphenol that is abundant in red wine and is reputed to underlie many of wine's health-related benefits. Interestingly, resveratrol seemed to be the most potent Sir2 activator of all of the plant polyphenols tested. The authors showed that this chemical prolonged the lifespan of yeast by approximately 70%. The extension of longevity was entirely dependent on Sir2 — yeast strains deficient in this enzyme did not benefit from resveratrol treatment.
Could plant polyphenols be the long-sought elixir of youth? Previous studies have hinted that these compounds have several potential health benefits, especially in protecting against age-related maladies such as cancer, neurodegeneration and atherosclerosis9. Interestingly, caloric restriction is also thought to protect against these diseases. But caution is warranted before endorsing a strict Cabernet Sauvignon-based regimen. First, the concentration-dependent effects of resveratrol as observed by Howitz et al. were complicated. At relatively low doses these molecules stimulated sirtuin activity, but, at least in certain assays, higher doses had the opposite effect. This is not an ideal characteristic for a pharmaceutical drug. Second, and more importantly, life extension in yeast is a long way from life extension in higher organisms. Indeed, how sirtuins function in mammalian ageing is not yet known.
Further unravelling of the molecular signalling pathways that accompany caloric restriction should provide clues to other potential targets for drug development. In a strange way, however, the study by Howitz et al. suggests that Ponce de León's misbegotten quest for a fountain of youth surrounded by flowering plants was not so delusional after all. The explorer's only mistake was that he kept sampling the waters, when he should have been testing the plants.
