This is the proceeding summary and the slide deck from my presentation on Nutrition and Aging at the 2023 ACVIM Forum in Philadelphia.

Effect of Nutritional Interventions on Aging

INTRODUCTION
While the clinical phenotype of aging is readily identifiable, a precise definition of this ubiquitous phenomenon is challenging. A useful pragmatic definition is the accumulation of changes over time that increase an individual’s susceptibility to disability, disease, and death. The passage of time is a key factor, yet it is not the primary driver of aging. Factors such as genetics, environmental exposures, and nutrition also play critical roles. 

The cellular and molecular changes characteristic of mammalian aging are often grouped into categories known as hallmarks of aging (Figure 1).¹ Though not exhaustive, this scheme provides useful starting points for investigations into the mechanisms of aging and for evaluation of interventions to influence this process and mitigate the negative health outcomes resulting from it. 

Figure 1. Hallmarks of aging.¹

The scientific understanding of these hallmarks, and how they can be manipulated, has reached a point at which aging can reasonably be viewed as a modifiable risk factor for disability, disease, and death. The length of time an individual lives (lifespan) and the proportion of that life free of significant age-associated disability or disease (healthspan) can be extended by targeting the underlying mechanisms of aging.

Interventions so far demonstrated to increase lifespan and healthspan in animal models include modifications of activity level and environmental conditions, pharmaceuticals, and diet.

There are various ways in which diet can potentially impact health and longevity-

• Dietary interventions to prevent and treat age-associated disease (e.g. dietary therapy of chronic kidney disease in cats)²
• Optimization of diet to match changing nutritional requirements throughout the lifecycle (e.g. differences in the protein content of diets formulated for puppies and for geriatric dogs)³
• Optimization of diet for individual health (e.g. potential applications of nutrigenomics and metabolomics)⁴
• Extension of lifespan and delay or prevention of age-associated disease through dietary interventions targeting specific hallmarks of aging

The last approach has been the focus of extensive research since at least the early twentieth century, when it was first shown that reduced food intake extend lifespan in rats.⁵ The field has progressed from rather crude, trial-and-error methods to the evaluation of specific cellular and molecular mechanisms that can be stimulated and inhibited to achieve substantial changes in median and maximum lifespan and in health. The primary, though by no means only, hallmark of aging targeted by dietary interventions is dysregulated nutrient sensing.⁶

NUTRIENT SENSING AND AGING
Nutrient sensing involves a complex network that detects the availability of nutrients and energy and regulates cellular growth and metabolism, apoptosis and autophagy, protein synthesis, and other processes depending on the available nutritional resources. The functioning of these mechanisms changes in a consistent pattern with aging, though the rate of this change differs between species and even between individuals. These changes are a key element in the degenerative process of aging and the increasing susceptibility to disease and death. 

Critical pathways maintaining an appropriate balance between the energy and nutrients taken in and the function and maintenance of an organism are highly conserved across organisms as evolutionarily distant as flatworms, fruit flies, rodents, dogs and cats, and humans. An example is the target-of-rapamycin (TOR) protein kinase, homologues of which regulates cell proliferation, protein synthesis, and many other anabolic processes in yeast just as in mammals.^5,6

A recurring motif in aging biology is that nutritional stress, such as reduced availability of calories or specific nutrients, can suppress some nutrient sensing pathways and activate others, with a net effect of inhibiting age-related disease and extending lifespan. These pathways are complex and interact extensively with each other and with many other physiologic processes, so simple generalizations are inherently problematic. However, sufficiently consistent  patterns have emerged in a variety of organisms to allow a broad but useful characterization of some key elements and their influence on lifespan and healthspan when activated or suppressed by dietary interventions. Table 1 provides a brief list of some key regulators in these pathways and their typical impact on lifespan when activated or suppressed.

Table 1.  Key regulators of nutrient sensing pathways.

Regulator	Activities	Effects on Lifespan
“Bad Guys”
mTOR (mechanistic target of rapamycin)	Increases cell growth, cell division, protein synthesisPromotes anabolism	Activity increases with ageHigh activity promotes aging and age-related diseaseSuppression increases lifespan
GH/IGF-1 (growth hormone; insulin-like growth factor 1)	Promotes anabolismStimulates mTORInhibits FOXO	High activity reduces lifespanSuppression increases lifespan
“Good Guys”
AMPK (AMP-activated protein kinase)	Promotes catabolism and suppresses anabolismSuppresses mTORStimulates FOXO and SIRT	Activity declines with ageHigh activity increases lifespan
FOXO (forkhead box O transcription factors)	Coordinates nutritional stress responseRegulates energy metabolism, cellular proliferation and apoptosis, redox balance, autophagyInhibits mTOR	High activity increases lifespan
SIRT (NAD+-dependent sirtuin deacetylases)	Regulates energy metabolism and balance between anabolism and catabolismInhibits mTORStimulates FOXO	High activity increases lifespan

DIETARY INTERVENTIONS TO INCREASE LIFESPAN

Caloric Restriction (CR)
Defined as significant reduction in calorie intake (typically 20-50%) without malnutrition or change in macronutrient ratios, CR has been consistently shown to increase lifespan and reduce the burden of age-related disease in multiple species, including rats and mice, primates, and dogs.^5,7,8 The effects of this intervention are broad, but suppression of mTOR and activation of AMPK and SIRT are considered central mechanisms in this approach.^6,9 Pharmacologic CR mimetics targeting these mechanisms have also extended lifespan and healthspan in some studies.¹⁰

CR is the most consistently effective dietary intervention for extending lifespan and healthspan. However, there are limitations to this approach. Some studies involved concurrent protein restriction or control animals with obesity and metabolic dysfunction, which complicates determination of the true effect size of pure CR. Genetic background also influences the impact of CR, and some strains of mice show no benefit or even reduction in lifespan.⁵ Such an extreme intervention is also too impractical and potentially dangerous for routine use in humans or companion animals.

Protein and Selective Amino Acid Restriction
Rodent studies have demonstrated extension of lifespan with general protein restriction and with selective restriction of sulfur-containing amino acids (e.g. methionine, cysteine) and branched-chain amino acids (BCAA; e.g. leucine, valine). Some of these have also involved CR, but benefits have been seen with isocaloric protein and amino acid restriction, though the effect size is considerably smaller than that of CR. Inhibition of GH/IGF-1 and mTOR appear to be the main mechanisms for this effect.^5,11

Timing of Feeding
Manipulations of the timing of feeding, including fasting regimes, time-limited feeding, or cyclic intermittent CR have all been shown to extend lifespan. Most of these regimes amount to a form of CR, but they may be more sustainable in real-world use. A few studies of isocaloric manipulations of the timing of feeding have also shown positive effects on glucose, insulin, and IGF-1 and the induction of short-term ketosis, all of which might have beneficial effects on lifespan and healthspan, though this has not be conclusively demonstrated.⁵

Ketogenic Diets (KD)
Carbohydrates-restricted diets which induce ketogenesis, as well as direct administration of some ketone bodies, have been shown in a few studies to increase lifespan and healthspan in mice and invertebrate models of aging. Such diets may mimic the effect of CR in shifting metabolism away from glycolysis and towards fatty-acid oxidation. Some KD formulations may also be protein-restricted and inhibit mTOR activity. The evidence supporting the effect of KD on longevity, however, is currently quite limited.

DIETARY INTERVENTIONS FOR LONGEVTIY IN COMPANION ANIMALS
Extension of lifespan and healthspan by CR has been demonstrated in dogs, and there is some limited evidence that other dietary manipulations might increase longevity in cats.^7,12 However, the potential impact of CR, protein restriction, and ketogenic diets on aging in companion animals is largely unknown, and most strategies are based on speculation and extrapolation from research in rodents or other laboratory animals.

Unfortunately, strong claims for lifespan extension have been made for various dietary interventions, including raw diets, “fresh food,” and ketogenic diets. These claims are not based on robust, target-species research and present a misleading picture of the state of the science in this area. The belief that an optimal diet for longevity is known and can be formulated for dogs and cats, or even for individual animals, is unjustified and places an unfair and unsupportable burden on pet owners to choose the “right” food. 

            Future studies investigating the hallmarks of aging and their response to dietary manipulations as well as clinical studies directly assessing the impact of novel feeding strategies on lifespan and healthspan are needed before clinical recommendations regarding diet and longevity can be made with confidence. Until that evidence is available, it is most appropriate to continue offering current, evidence-based dietary recommendations.

REFERENCES

1.        López-Otín C, et al; Hallmarks of aging: An expanding universe. Cell 2023;186(2):243.

2.        Ross SJ, et al; Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats. J Am Vet Med Assoc 2006;229(6):949.

3.        Laflamme DP; Nutrition for aging cats and dogs and the importance of body condition. Vet Clin North Am Small Anim Pract 2005;35(3):713.

4.        Ordovas JM, et al; Personalized nutrition and healthy aging. Nutr Rev 2020;78(12 Suppl 2):58.

5.        Lee MB, et al; Antiaging diets: Separating fact from fiction. Science 2021;374(6570).

6.        Pignatti C, et al; Nutrients and Pathways that Regulate Health Span and Life Span. Geriatr 2020;5(4):1.

7.        Lawler DF, et al; Diet restriction and ageing in the dog: major observations over two decades. Br J Nutr2008;99(4):793.

8.        Pifferi F, et al; Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies. Prog Neuropsychopharmacol Biol Psychiatry. 2019;95. 

9.        Green CL, et al; Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol. 2022;23(1):56.

10.      Madeo F, et al; Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metab. 2019;29(3):592.

11.      Brandhorst S, et al; Protein Quantity and Source, Fasting-Mimicking Diets, and Longevity. Adv Nutr. 2019;10(Suppl 4):S340.

12.      Cupp C, et al; Effect of Nutritional Interventions on Longevity of Senior Cats. Int Jounrla Appl Res Vet Med. 2007;5(3):133.