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.
https://honeysrealdogfood.com/wp-content/uploads/2020/07/Honeys-Raw-Proof-Report.pdf
This is packaged to look like research, but it isn’t. No blinding, no randomization, no control diet, no objective analysis just (to paraphrase) “we looked at the dogs and weighed them and everything seemed ok.” This kind of faux research is part of the problem with raw diets and their advocates. Ifg th3y want to prove their claims, they need to conduct actual research according to all the usual methods and standards of scientific studies, not just package uncontrolled observations and case studies as if thy were “trials.”
gov funded study of rapamycin to see if it extends life in dogs like it does lab animals may get canceled for lack of funds. https://www.nytimes.com/2024/01/11/health/dogs-longevity-aging.html the article pointed out the date of birth was estimated in the dog study. Dob would be known in mouse or human study. article is behind a pay wall so i will ask a chatbot about it for more information.
Dr. Arthur Malernee
@artmalernee
this article is behind a paywall. can you tell me anything about the subject
Grok
@grok
I would be happy to help you with that! However, I need the subject or the title of the article to provide you with relevant information. Please provide me with the subject or title, and I’ll do my best to assist you.
Dr. Arthur Malernee
@artmalernee
https://www.nytimes.com/2024/01/11/health/dogs-longevity-aging.html
Grok
@grok
It seems like you’re trying to share a New York Times article with me. Unfortunately, I don’t have access to the internet content through a given URL. However, I can still try to provide you with information on the topic.
The Dog Aging Project, a large-scale study on canine aging, is currently under review for continued funding. Scientists are working to understand the factors that contribute to a dog’s lifespan and how to improve their overall health. The project has enrolled tens of thousands of dogs of various breeds and sizes, with the goal of creating an open-source dataset for veterinarians and scientists to better assess a dog’s aging process.
While the Dog Aging Project continues, recent news has put the spotlight on Bobi, a purebred Rafeiro do Alentejo, who was recognized by Guinness World Records as the world’s oldest dog. However, his age has been under review due to concerns from veterinarians. Bobi celebrated his 31st birthday in 2023 and has received a great deal of attention for his longevity.
In summary, the Dog Aging Project and Bobi’s case have both contributed to our understanding of dog longevity and aging. Researchers hope to uncover more information to help our beloved pets live longer, healthier lives.
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Matt McClure
@matthewlmcclure
·
Jan 12
Hi Dr McKenzie!
Thank you for sharing this presentation. I was wondering if this research has any effect on the way you feed your own dogs (even though I’m aware that actual recommendations cannot be made until there are larger bodies of evidence to draw from). Are you tempted to try and increase your own pets’ longevity by manipulating feeding frequency or caloric intake?
I confess to being one of those owners on the search for the “right” (or at least the “most supported”) option for many aspects regarding the health of the new dog I hope to adopt soon. I made the rookie mistake of trying to be both my last dog’s owner and her (qualified) veterinarian, including being the one to administer all of her lymphoma chemotherapy and her final injection myself, and it has taken many years for me to recover from both the grief and the trauma regarding the pressure of those decisions! Now after 8 years I finally find myself far enough removed that the vacancy of a dog in my life is big enough to want to go there again, but needless to say I would like to do everything in my power to lengthen the time before the next heartbreak! I thought you might feel similarly given your recent focus on longevity.
The rescue dog I currently have my heart on is a 6mo shepherd cross, so that has me thinking about supporting his growth, joint health, (maybe immune function), and especially about the risks of GDV. I stopped practicing a while ago so I may be out-of-step with the latest recommendations, but traditionally the advice was smaller meals that don’t swell in the stomach, so that the ligaments holding the stomach in place do not become stretched. This can definitely be supported by my other major goal and interest, which is behaviour/training (I am very keen to develop my skills in cooperative care training). I was considering that rather than feeding him large meals, his daily allowance would be fed to him throughout the day through his training regimes (plus enrichment activities).
However, this would obviously negate any potential longevity benefits achievable from alternative practices like intermittent fasting. Would the feeding of a low-calorie, high-nutrient-concentration diet (eg Hills w/d) be a good alternative, do you think?
Obviously, the most important factor at the end of the day is quality of life, and I would feel a bit hypocritical and selfish optimising my dog’s life for longevity over enjoyment, when I don’t even commit to doing such things for my own health. (Of course, avoiding obesity has quality-of-life benefits too).
I’d love to hear your thoughts (even though they’ll probably be “We can’t say yet” lol). Also sorry for the long message – I thought about getting to the point quicker lol, but wanted to give you some context for why I was asking. I know being asked for recommendations must get frustrating after you’ve explained when and why you can’t give them, but also sometimes we just want to do the best we can with the information we have until the rest comes along 🙂
Thank you for your work!!
Thank you for the comment.
As you say, there is more we don’t know than we do know at this stage, so any recommendation has to be tentative, and we have to be ready to give up even cherished ideas as more data comes in. I think the most confident thing we can say now is that dogs that are a healthy body weight, which generally means leaner than our typical mental image of a dog, tend to have an advantage in terms of health and longevity. For larger breeds, like a GSD< there is good evidence for feeding a large-breed puppy food until full growth (the most significant difference is probably lower calorie density and also potentially lower amounts of calcium). Less clear but still reasonable for GDV prevention is > 1 meal per day (not clear if more than 2-3 is worthwhile), not feeding shortly before exercise, and slower eating (food puzzles, food balls, etc.). Of course, I would definitely recommend a gastropexy as well!
The data on intermittent fasting are quite mixed in terms of both benefits and potential harms, and that is almost all research in humans, so not something I think is worth trying yet in dogs.
Other than that, lots of unknowns. I suspect fresh diets may have some benefits over kibble, but no real data to support that yet. I still feed my dogs a commercial kibble twice daily, using a feeder puzzle/ball for my big dog. Not committed to any particular brand, and there’s always some trial and error with a new dog to find a food they like and that they have good stools and general good condition while eating.
Good luck!
I would definitely recommend a gastropexy as well!>>>>> any prospective randomized trials that might support a pexy of a clinically healthy german shepard with no family history of gdv is a good idea? Retrospectively we have puppy food now for large dogs because the old puppy food was shown to be worse for large breeds than the adult formula. Humans were circumcised for years because of medical reasons. Ask any nicu nurse how that worked out. My favorite surgery in clinically healthy patients is doctors who take out apendix in people who are going to travel to places where no medical care might not be available to treat if appendix rupure occured. nnt nnh cost of treatment and caregiver burden are things to find out. Had a boarded veterianarian surgeon at a ce lecture boast that his mortality rate removing dog gallbladders was twenty five percent so whats true in dog not always true in humans. So would would love to ask a pexy surgeon who does a lot of them to estimate the four questions. Since i believe you are promoting pexy of a apparent clinically healthy ger shep with no family history help me come up with a estimate of the answer to the four questions
here is a chat bot trying to answer the four questions. The NNT it calculated all by itself apparently with data from dogs who already had a GDV. My NNT estimate for the ger shep that had no known GDV or family history would be over 1 in a 1000. If you are doing a OHE anyway and 80% of the dogs bred by a great dane breeder twist the NNT will be alot closer to Groks estimate in my opinion.
Dr. Arthur Malernee
@artmalernee
Can you provide information about the number needed to treat, the number needed to harm, the Cost of sugery and the caregiver burden for gastropexy prevention in dogs?
?
Grok
?
@grok
Certainly! Let’s dive into the data to provide you with the information you need.
Number Needed to Treat (NNT) and Number Needed to Harm (NNH): Based on the provided web snippets, it’s mentioned that a gastropexy can reduce the risk of recurrence of gastric dilatation and volvulus (GDV) from 55% to only 4%. This suggests that the NNT for gastropexy in dogs to prevent GDV is approximately 1.36 (100/55). However, it’s not explicitly stated in the sources, so we’ll consider this a rough estimate.
As for the NNH, the sources do not provide specific data on the number needed to harm. However, it’s mentioned that gastropexy is a relatively safe procedure with a low complication rate.
Cost of Surgery: The cost of a gastropexy in dogs varies depending on the type of procedure and the location. Here are some estimates from the web snippets:
Non-emergency gastropexy costs approximately $400.
Emergency gastropexy costs an average of $1,500 or more.
The cost of a prophylactic surgery (without emergency) is in the hundreds of dollars, while an emergency gastropexy can cost much more.
The cost of a gastropexy may be on the higher end if it involves laparoscopy, which requires specialized equipment and expertise.
Caregiver Burden: The caregiver burden for gastropexy in dogs is relatively low. After the surgery, dogs may need to wear an Elizabethan collar to prevent them from manipulating the incision site. They may also need to limit physical activities for a few weeks. However, the overall recovery time is relatively short, and most dogs can return to their normal activities within a few weeks.
In summary, the NNT for gastropexy in dogs is approximately 1.36, the NNH is not explicitly stated, the cost of surgery varies depending on the type of procedure and location, and the caregiver burden is relatively low.
Thanks so much for your thoughtful reply Dr McKenzie, and to Dr Malernee for your added thoughts re: gastropexy (even though my personal opinion about those generative text algorithms masquerading as AI is incredibly negative and a rant all on its own).
I realised once I posted the comment that I had been ambiguous in my mention of diets like w/d – I definitely plan on feeding a large breed puppy food until he is fully grown! I really appreciate you summarising that advice for me since I wasn’t sure if thinking had changed or been disproven.
My own biases and anecdotal experience will make me grapple with the gastropexy decision, which I hope I don’t come to regret one day (either way it goes). As Dr Malernee mentioned it would be a relatively easy prospect to do one at the same time as an OVH in a female dog, but he’s a desexed male so it would be a sole-purpose surgery. My biases come from being a genetic freak who doesn’t feel any pain relief from opioids (so all surgeries are incredibly painful, and – perhaps irrationally – I worry about our animal patients and the adequacy of our pain relief protocols for them) plus some concerns about the standards, training, control measures (or lack thereof) and outcomes from some of the vet clinics – and even human hospitals – in my area.
This can all be mitigated by careful clinic selection of course, but I also find the differences in ethical acceptability of surgical procedures across cultures to be very interesting and difficult for my conscience to confront. I know several countries in Europe perceive the rest of us to be very cruel for electively desexing animals, and as above I am averse to the idea of unnecessary surgeries and accompanying pain, but at the same time (in my anecdotal experience) the sheer numbers of significant emergency reproductive health issues I saw regularly in practice from undesexed animals makes me favour routine desexing. Plus, while the overbreeding/overpopulation/homeless animal problem is one that could and should be addressed culturally, I’m not optimistic. (I also just find many entire male dogs to constantly seem barely restrained and almost vibrating with frustrated energy/drive and therefore super annoying lol, but I know that’s not a good reason to favour widespread routine surgical practices!). I know this is a complicated matter especially now with studies on the effects on bones/joints and various cancers in certain breeds etc. I like that getting a rescue dog means not having to worry about the decision personally!
Anyway, it’s just interesting to me that some countries are ethically on board with (or feel they can justify on ethical grounds) declawing and tail docking and ear cropping, others ban these procedures along with prong collars etc but will allow desexing, electric collars, and even elective surgical insemination and repeated elective caesareans of greyhounds and purebreds shortly thereafter. Not that I consider appropriately-performed desexing on the same level as those other procedures/”training aids”, but then as mentioned there are countries/cultures that do.
Well, enough getting side-tracked! You’d be impressed (or maybe not lol) how much I can overthink even the choice of standard flat collar and various buckle types for a dog, so I really shouldn’t start bringing in all the bigger questions! From your encouragement I will seriously consider the preventative gastropexy if I am lucky enough to adopt him, and I’ll review the evidence for determining which dogs meet the criteria for benefitting from the procedure as it applies for whichever dog I may get if not.
Thanks again!